he forma ian and management

of mlddle ear granulation ti s e

in chronic ear isease
Peter S. Roland, MD

The for matio n of granulation tissue in the middl e ear
space begins with a break in the basement membrane of
surface epithelial cells (fig ure I). Inflamm atory cell s in
the underlying lamina prop ria traverse through the brok en
basement mem brane and enter the Iumen of the middle ear
space. The rupture of the basement memb rane and epithe-
Iial cell lining is caused by bacterial toxins, inflammatory
med iators praduced by ruptured Iysozymes, and the accu-
mulation of subepithelial fluid and vacuoles, all of which
exer t pressure on the surface epi thelium.
The second step in the forma tion of granulation tiss ue
occurs when a small piece of the hemia ted lamin a propria
extr udes thro ugh the ruptured area of the epithelial cell
surface (figure 2). The result of this extrusion is that the
affected tissue is no longer epi thelialized. In some cases,
angiogenic growth factors -such as endothelial grow th
facto r, tissue grow th factor s alpha and part icularly beta,
vasc ular endothelial grawth fac tor, and pros taglandin-
derived grawth factor-incite capillary budd ing, vasc ular
hyperpermeability, and fibrablast recruitment. If the
grow th of gran ulation tiss ue is vigorous and aggressive,
polyps can form (figure 3).
Following the rupture of the lamina propr ia into the
middle ear space , re-epithe lialization begins. Re-epith e-
lializat ion is a contin uous process, although it occ urs at
different rates and is often incom plete. When the epithe-
lium surro unds a polyp , it ca n become metaplastic.
Microsectioning of these polyps genera lly reveals the
presence of a var iety of different types of epitheIial
surfaces in diffe rent portions of the polyp. The presence
or absenee of a significant amo unt of kera tinizing epithe-
lium on a polyp surface during biopsy analysis can pro-
vide clues to the polyp's etiology . The presence of signifi-
cant kerati nizing epithelium indicates that the cause of the
polyp is a cho lesteatoma, as opposed to a pure ly infec -
tious pracess. On the other hand , the abse nce of squamo us
kerati nizi ng epitheli um is a fai rly relia ble sign that no
cholesteatoma is present.
Tympano stomy-t ube-related granu lat ion tissue
Incidenee. Granulation tiss ue is invo lved in several types
of chron ic ear disease, particularly in patients who have
tympanostom y tubes. Kay et al perform ed a meta- analy-
sis of more than 7,000 ears and found that the mean
incidenee of granulation tissue in pat ients with tymp an-
ostomy tubes was slightly less than 5 %.1 Of these, 8.1 %
req uired surgic al debridement. El-B itar et al found that
the incidenee of granulation tissue was 13.8% in tyrn -
panostomy tubes that had been in place for 2 to 3 years and
more than 40 % in tubes that had been in place for more
than 5 years.? They also noted that children who were
older than 7 years were much more likely to have granu-
lation tissue than were youn ger children, regar dless of
how long the tubes had been in place.
Etiology. The etiology of tympanostomy-tube-related
gra nulation tissue is still disputed. In some cases, of
cour se, its develo pment is almost cer tainly the resu lt of
the actual middl e eal' infection itself. Granulation tissue
might also arise as adireet response to the presence of the
fore ign body in the tymp anic membra ne, OI' it might
represent a direet response to trapped squamous epithe -
lium that has become lodged between the flange of the
Figure 1. The forma tiall of granulation tissue begins when
inflammatory eelis (arrow) traverse from the lamina propria
throug h a break in the basement membra ne of surface epithelial
eelis and ente r the lumen ofthe middle ear space. (Reprinted with
permission from Caye-Thomasen P, Hermansson A, Tos M,
Prellner K. Polyp pathogenesis-A histopathological study in
experime ntal otitis media. Acta Otolaryngol 1995;115:76-82.
[www.tandf.no/otol),

ENT-Ear, Nose & Throat Journal · Suppl 1 • January 2004 ·5

 ROLAND

tube and the tympanic mem-

brane. Post suggested that
tympanostomy-tube-related
granulation tissue might be
related to the development
ofbacterial biofilms that ad-
here to the surface of the
tube.'
Consequences. There are
several potential conse-
quences of tympanostomy- Figure 2. A small piece ofherniated lamina propria (arrows) extrudes through the ruptured area
tube-related granulation tis- ofthe epithelial cell surface, leaving an unepithelialized piece oftissue in the lumen ofthe middle
sue . One is that it might im- eal'space. (Reprinted with perrnission from Caye-Thomasen P, Herrnansson A, Tos M , PreIlner
pede the delivery of topieal K.Polyppathogenesis-A histopathological studyinexperimental otitismedia. ActaOtolaryngol
antibiotic solution to the site 1995;115:76-82. [www.tandf.no/otoj).
of infection so that the ear-
drop cannot penetrate into the middle ear space, which, of myringitis is, in effect, a granulation tissue disease-that
course, would result in a treatment failure. Another com- is, granulation tissue is essentially its only manifestation.
plication is that the granulation tissue can cause bloody
otorrhea. This in itself is not serious, but it can alarm the Control and management
child 's parents and lead them to seek emergency treat- The control and management of granulation tissue in-
ment , which significantly drives up the cost of care . volves the use of four modalities: aural toilet, anti-
Finally, over long periods of time, granulation tissue can infectives, steroids, and cautery or debridement.
fibrose and lead to permanent searring. Aural toi/et. The easiest method of aural toilet is irri-
gation, which, of course, can be performed by virtually
Granulation tissue in other types of chronic anyone in any setting . The best results are achieved with
ear disease one or two syringefuls or bulbfuls of either full-strength
Meyerhoff et al reported that granulation tissue develops (3%) or half-strength hydrogen peroxide, which is safe
in 94% of all cases of chronic suppurative otitis media and generally painless. Flushing of the ear should take
(CSOM), usually in the epitympanum, and in 100% of place IS to 20 minutes prior to the administration of
cases of CSOM that are characterized by intracranial therapeutic eardrops so that the irrigation solution has had
complications." Granulation tissue also develops in many sufficient time to dissipate. Once the ear is dry, the
cases of chronic otitis externa. Finally, chronic granular therapeutic eardrops will be able to penetrate to the source
of the granulation tissue.
Anti-infectives. The fluoroquinolone and the amino-
glycoside antibiotics are the mainstays of the manage-
ment of chronic granulation tissue because the ultimate
etiology of the abnormality is infectious. For middle ear
disease, the quinolones are preferred because they lack
the potential for ototoxicity.
Topieal antibiotics have a great advantage over other
dosage forms with respeet to the higher concentration of
medication that can be delivered. For example, a 3- to 5-
drop dose of a topieal antibiotic delivers a total of ap-
proximately 1 to 1.5 mg of medication, but the concentra-
tion ofthat medication is 3,000 ug/ml. This concentration
exceeds the minimum inhibitory concentration necessary
to eradicate any known relevant pathogens. The concen-
tration of systemic antibiotics that can be delivered to
Figure 3. Vigorous and aggressive growth of granulation tissue middle ear fluid is much lower. For example, administra-
results in polyp formation . (Reprinted with perrnission from tion of high-dose amoxicillin-90 to 100 mg/kg/day-
Caye-Thomasen P, Herrnansson A, Tos M, PreIlner K. Polyp delivers a concentration of only 8 to 10 ug/ml to the
pathogenesis-A histopathological study in experimental otitis middle ear fluid. A similar dose of cefuroxime delivers 2
media.Acta Otolaryngol1995; 115:76-82. [www.tandf.no/otoj). to 4 ug/rnl to the middle ear fluid. Pediatricians are

6 • Volume 83 • Suppl 1
 THE FORMATiaN AND MANAGEMENT OF MIDDLE EAR GRANULATION TISSUE IN CHRONIC EAR DISEASE

enamored with intramus-

cular ceftriaxone because
100
it delivers a concentration • Ciprellexacin/dexamethasene
as high as 25 to 30 ug/rnl 90 -
. Ollexaeln
to the middle ear fluid, but 80
even this concentration .l!l 70
pales in significance when t:
al
:;:; 60 -
compared with the 3,000 ell
ug/rnl achieved with topi- _C. 50 - p= 0.058
o
eal drops. '$. 40 -
Steroids. For many 30 -
years, most otolaryngol-
20
ogists have held as an ar-
ticle of faith the belief that 10
steroids are important in
suppressing, eliminating, 3 11 18
and preventing granula- Day
tion tissue. We are not
alone; dermatologists, Figure 4. Chart shows that ciprofloxacinldexamethasone was significantly more effective than
plastic surgeons, veteri- ofloxacin alone in eradicating granulation tissue in 90 children with acute otitis media with otorrhea
at JJ and J8 days from the initiation of treatment,
narians, and a wide vari-
ety of other physicians
have long believed this to
be the case. The more potent steroids are preferred over inexpensive. Another of their virtues is that they adhere to
the weaker ones . moist surfaces, so their dwell-time in and around the
Several animaI studies have found that steraids are infective tissue appears to be relatively prolonged. These
effective in controlling keloids and hypertrophic scar- powders are made up of a variety of different combinations
ring' and in reducing angiogenesis and subsequent granu- of an antibiotic (a quinolone, a sulfonamide, or chloram-
lation ." In rabbits, Hashimoto et al showed that steraids phenicol), an antifungal (clotrimazole or amphotericin B),
suppress the formation of granulation tissue (I) by reduc- and a steraid (dexamethasone or hydrocortisone).
ing vascular permeability, (2) by decreasing extravasa- Cautery, Chemical cautery is usually performed with
tion and the migration of inflammatory cells to the site of silver nitrate, although other agents such as trichloroace-
infection, (3) by inhibiting the production of a variety of tic acid are sometimes used . Keep in mind, however, that
chemotactic factors (especially complement factors and chemical cautery is in effect a burn, and control over the
lymphocyte-derived factors), and (4) by acting on grawth depth and severity of that burn is somewhat limited. Every
factors such as vascular endothelial growth factor and few years, we see a report of a case of facial nerve
transforming growth factor bera." paralysis that occurred because the cauterizing agent,
Steroids appear to be effective in humans, as weIl. We usually silver nitrate, was applied too aggressively at the
conducted a randomized, controlled, double-blind drug wrang site .
comparison study of 599 children with patent tym- Debridement. Debridement can be performed in the
panostomy tubes and acute otitis media with otorrhea of office setting with a micrascope and small Bellucci's
3 weeks' or less duration. " Patients were treated with scissors. Avulsing a polyp is usually not recommended,
either a quinolone pIus a steroid (ciprofloxacin/dexa- because when it is removed, the otolaryngologist might
methasone at4 drops twice aday for7 days) or aquinolone find that the stapes is attached to the end of the polyp.
alone (ofloxacin at 5 drops twice a day for 10 days). Not Using sharp techniques will help avoid injury. Tyrnpano-
only did the combination product prove to be significantly mastoid surgery for chronic otitis media is, in effect, an
more effective in establishing clinical and microbiologic aggressive form of debridement, and it is quite effective.
cure in aU patients,? it was also significantly more effec-
tive in treating asubgroup of 90 children who had granu- Summary
lation tissue at baseline (figure 4).s Granulation tissue is an important pathogenic feature of
Powders. Topieal powders are also widely used to all types of chronic ear disease, and it can be contraUed
contral granulation tissue in any of the chronic ear condi- and treated with good aura I toilet, appropriate antibiotic
tions. They can be administered twice a week to twice a therapy, topieal steroids, and chemical cautery or surgical
month in the office or at home, and they are relatively debridement.

ENT·Ear, Nose & Throat reumat- Suppl 1 • January 2004·7

 ROLAND
Ref erences
I. Kay DJ, Nelson M, Rosenfeld RM. Meta-analysis of tym-
panostomy tube sequelae. Otolaryngol Head Neck Surg 200 1;
124:374-80.
2. EI-Bitar MA, Pena MT, Choi SS, Zalzal GH. Retained ventilation
tubes: Should they be removed at2 years? Arch Otolaryngol Head
Neck Surg 2002; 128:1357-60.
3. Post JC. Direet evidence of bacterial biofilms in otitis media.
Laryngoscope 200 I; III :2083-94.
4. Meyerhoff WL, Kim CS, Paparella MM. Pathology of chronic
otitis media. Ann Otol Rhinol LaryngoI1 978;87:749-60.
5. Bertone AL. Managemen t of exuberant granulation tissue. Vet
Clin North Am Equin e Pract 1989;5:551-62.
8 • Voluma 83 • Suppl 1
6. Hashimoto I, Nakanishi H, Shono Y, et al. Angio static effects of
corticosteroid on wound healing of the rabbit ear. J Med Invest
2002;49:61-6.
7. Roland PS, Kreisler LS, Reese B, et al. Topieal ciprofloxacin/
dexamethasone otic suspension is superior to ofloxacin otic
solution in the treatment of childr en with acute otitis media with
otorrhea through tympanostom y tubes. Pediatrics 2004;113:40-6.
8. Roland PS, Dohar JE, Lanier BJ, et al. Ciprofloxacin/dexameth a-
sone versus ofloxacin for granulation tissue in AOMT patients.
Presented at the annual meeting of the American Academy of
Otolaryngology-Head and Neck Surgery; Sept. 22, 2003 ; Or-
lando , FIa.