Tonsillectomy

Tonsillectomy Appears to Protect Against Tonsil Cancer

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Having your tonsils out will get you ice cream ― and perhaps protection from tonsil cancer. The finding from a large Danish population-based study seems intuitive, but really had not been shown before.

But lead researcher Carole Fakhry, MD, of Johns Hopkins School of Medicine, Baltimore, Maryland, said she “would not encourage people to get a tonsillectomy” in the hope of reducing their risk for this type of oral cancer, which is rare. However, a “side benefit” of tonsillectomy might be the reduction in risk for these cancers, she told Medscape Medical News.

The study was published online April 20 in Cancer Prevention Research.
The incidence of oropharyngeal carcinoma, which includes cancers arising from the tonsils, oropharynx, pharynx, Waldeyers’ ring, and branchial cleft, is increasing globally, particularly in younger age groups, driven largely by sexually transmitted human papillomavirus (HPV) infection, Dr Fakhry and colleagues note in their article.

For example, about 77% of tonsil cancers in Denmark, which is the data source for the new study, occurring between 2000 and 2010 were related to HPV. At the same time, tonsillectomy for hypertrophic tonsils and recurrent tonsillitis has “lost previously held general acceptance,” they point out about Western countries.

“We are asked this question all of the time by patients: ‘Could I have prevented this [oropharyngeal cancer] by having a tonsillectomy?’ ” Dr Fakhry said.

So she and her colleagues decided to investigate.

Using data from 1977 to 2012 on more than 3.8 million adults in the Danish Cancer Registry, they analyzed the incidence of tonsillectomies and oropharyngeal carcinoma and whether tonsillectomy reduces the future risk for oropharyngeal carcinoma.
Since 1977, the incidence of tonsillectomy has fallen significantly (P < .001), most markedly after 1995, they report. The rate of tonsillectomy has declined by 1.1% annually, on average. During a 35-year period, this corresponds to a 33.8% decrease in the incidence of tonsillectomies.

During the same period, the incidence of oropharyngeal carcinoma increased “dramatically,” the researchers report.

Importantly, tonsillectomy was not associated with the risk for oropharyngeal carcinoma or cancer of other anatomic sites, including the base of tongue. However, tonsillectomy was associated with a 60% reduction in risk for tonsil cancer (rate ratio [RR], 0.40; 95% confidence interval [CI], 0.22 – 0.70).

“Notably,” say the researchers, the risk for diagnosis of tonsil carcinoma before age 60 years was significantly reduced after tonsillectomy (adjusted RR, 0.15; 95% CI, 0.06 – 0.41).

Tonsillectomy within 1 year of diagnosis of tonsil carcinoma was associated with significantly improved overall survival (hazard ratio, 0.53; 95% CI, 0.38 – 0.74).

“Tonsillectomy likely reduces the palatine lymphoid tissue susceptible to carcinogenic factors, and subsequent potential for malignant transformation,” the researchers say.

But again, they do not recommend prophylactic tonsillectomy for the general population. For one thing, tonsil carcinoma is rare, as noted above. If a biomarker of “high predictive value” for the development of oropharyngeal cancer could be identified, people with such a marker might benefit from tonsillectomy, although that would require study, they suggest.

“If early tonsil lesions could be identified through a combination of biomarkers for risk stratification, imaging, and cytologic evaluation, then tonsillectomy in a select well-defined population may reduce the incidence of tonsil carcinoma,” they add.

Limitations of the study include the lack of some “clinically relevant information,” including HPV tumor status, stage, and tobacco use, which introduces the potential for residual confounding, the researchers note.

Also, the limited number of oropharyngeal carcinoma cases overall (n = 52) and of tonsil carcinomas (n = 12) following tonsillectomy could imply that the observed associations were by chance. “Although the estimates of the effect of tonsillectomy may have low precision and relatively wide CIs, the significant point estimates are far from null and highly significant, therefore supporting a true association,” they say.

This study “provides the first insight into the association of tonsillectomy with risk of oropharyngeal cancers,” Anil Chaturvedi, PhD, with the Division of Cancer Epidemiology at the National Institutes of Health, notes in an accompanying editorial.

It shows “an ecologic correlation” between declining incidence of tonsillectomies in Denmark and rising oropharyngeal cancer incidence over time, he points out. Still, the question remains regarding the extent to which a decline in tonsillectomies has contributed to the rise in tonsil cancer incidence in recent years, he adds.

Echoing the authors, Dr Chaturvedi says, “at this time, prophylactic tonsillectomies should not be considered as a secondary prevention strategy for oropharyngeal cancers.”

“Although a common surgical procedure, tonsillectomy is not without minor complications, such as postoperative bleeding, pain, and nausea, as well as major complications, such as hemorrhage and death,” he writes.

FDA Drug Safety Communication: Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death.

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The U.S. Food and Drug Administration (FDA) is reviewing reports of children who developed serious adverse effects or died after taking codeine for pain relief after tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. Recently, three pediatric deaths and one non-fatal but life-threatening case of respiratory depression were documented in the medical literature1,2 (see Data Summary below). These children (ages two to five) had evidence of an inherited (genetic) ability to convert codeine into life-threatening or fatal amounts of morphine in the body. All children had received doses of codeine that were within the typical dose range.

Facts about codeine
 

 
  • An opioid pain reliever used to treat mild to moderately severe pain
  • Also used, usually in combination with other medications, to reduce coughing
  • Available as a single-ingredient product, or in combination with acetaminophen or  aspirin, and in some cough and cold medications

 

When codeine is ingested, it is converted to morphine in the liver by an enzyme called cytochrome P450 2D6 (CYP2D6). Some people have DNA variations that make this enzyme more active, causing codeine to be converted to morphine faster and more completely than in other people. These “ultra-rapid metabolizers” are more likely to have higher than normal amounts of morphine in their blood after taking codeine. High levels of morphine can result in breathing difficulty, which may be fatal. Taking codeine after tonsillectomy and/or adenoidectomy may increase the risk for breathing problems and death in children who are “ultra-rapid metabolizers.” The estimated number of “ultra-rapid metabolizers” is generally 1 to 7 per 100 people, but may be as high as 28 per 100 people in some ethnic groups (see Table 1 below).

FDA is currently conducting a safety review of codeine to determine if there are additional cases of inadvertent overdose or death in children taking codeine, and if these adverse events occur during treatment of other kinds of pain, such as post-operative pain following other types of surgery or procedures.

Health care professionals should be aware of the risks of using codeine in children, particularly in those who have undergone tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. If prescribing codeine-containing drugs, the lowest effective dose for the shortest period of time should be used on an as-needed basis (i.e., not scheduled around the clock).

Parents and caregivers who observe unusual sleepiness, confusion, or difficult or noisy breathing in their child should stop giving their child codeine and seek medical attention immediately, as these are signs of overdose.

FDA will update the public with more information once it has completed its review.

Additional Information for Parents and Caregivers

  • Certain children may be at risk for life-threatening side effects, such as breathing difficulty, or death when taking codeine for pain relief after tonsillectomy or adenoidectomy. This can occur even with use of codeine at recommended doses.
  • Codeine is usually prescribed on an “AS NEEDED” basis. Do not administer codeine to the child on a regular basis UNLESS the child requires the drug. Do not administer more than six (6) doses per day.
  • Signs of serious side effects of codeine in children can include unusual sleepiness, confusion, and difficult or noisy breathing. If your child shows these signs, stop giving your child codeine and seek medical attention immediately by taking your child to the emergency room or calling 911.
  • Talk to your child’s health care professional if you have any questions or concerns about codeine.
  • Report side effects from codeine to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of this page.

Additional Information for Health Care Professionals 

  • Life-threatening adverse events and death have occurred in certain children who received codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. These children had evidence of being “ultra-rapid metabolizers” of substrates of cytochrome P450 2D6 (CYP2D6), including codeine.
  • If prescribing codeine-containing drugs, use the lowest effective dose for the shortest period of time on an as-needed basis (i.e., not scheduled around the clock).
  • Counsel parents and caregivers on how to recognize the signs of morphine toxicity, and advise them to stop giving the child codeine and to seek medical attention immediately if their child is exhibiting these signs.
  • FDA-cleared tests are available for determining a patient’s CYP2D6 genotype.
  • The estimated number of ultra-rapid metabolizers varies among different racial/ethnic groups (see Table 1below).
  • Consider prescribing alternative analgesics for children undergoing tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome.
  • Report adverse events involving codeine to the FDA MedWatch program using the information in the “Contact FDA” box at the bottom of this page.

Data Summary

Recently, three deaths and one case of severe respiratory depression were reported in children who received codeine after undergoing tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. The children ranged in age from two to five years old. The three deaths occurred in children who had evidence of being “ultra-rapid metabolizers” of substrates of the cytochrome P450 isoenzyme 2D6 (including codeine), and the life-threatening case occurred in a child who was an extensive metabolizer. All children received doses of codeine that were within the typical dose range. In these cases, signs of morphine toxicity developed within one to two days after starting codeine. The post-mortem morphine concentrations in the three children who died1,2 were substantially higher than the typical therapeutic range.3

FDA is conducting a review to determine if there are additional cases of inadvertent overdose or death in children taking codeine, and if these adverse events occurred during treatment of other kinds of pain such as post-operative pain following other types of surgery or procedures. FDA will update the public when more information is available.
Table 1. Prevalence of Ultra-rapid Metabolizers in Different Populations

Population UM Genotypes/Phenotypes
(↑ Activity)		 Prevalence %
(UM/Total n)
African/Ethiopian4 UM (active duplicate genes) 29% (35/122)
African American5, 6 UM (three active duplicate genes) 3.4% (3/87)
6.5% (60/919)
Asian7, 8, 9 UM (active duplicate genes) 1.2% (5/400)
2%
Caucasian5, 6 UM (three active duplicate genes) 3.6% (33/919) 6.5% (18/275)
Greek10 CYP2D6*2xN/UM 6.0% (17/283)
Hungarian11 UM (active duplicate genes) 1.9%
Northern European10, 12 UM (active duplicate genes) 1-2%

UM = ultra-rapid metabolizer; CYP2D6 = cytochrome P450 2D6
References

  1. Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med 2009;361:827-8.
  2. Kelly LE, Rieder M, van den Anker J, Malkin B, Ross C, Neely MN, et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics 2012;129:e1343-7.
  3. Williams DG, Patel A, Howard RF. Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. Br J Anaesth 2002;89:839-45.
  4. Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F, Ingelman-Sundberg M. Frequent distribution of ultrarapid metabolizers of debrisoquine in an ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996;278:441-6.
  5. Kohlrausch FB, Gama CS, Lobato MI, Belmonte-de-Abreu P, Gesteira A, Barros F, et al. Molecular diversity at the CYP2D6 locus in healthy and schizophrenic southern Brazilians. Pharmacogenomics 2009;10:1457-66.
  6. Gaedigk A, Fuhr U, Johnson C, Bérard LA, Bradford D, Leeder JS. CYP2D7-2D6 hybrid tandems: identification of novel CYP2D6 duplication arrangements and implications for phenotype prediction. Pharmacogenomics 2010;11:43-53.
  7. Ji L, Pan S, Marti-Jaun J, Hänseler E, Rentsch K, Hersberger M. Single-step assays to analyze CYP2D6 gene polymorphisms in Asians: allele frequencies and a novel *14B allele in mainland Chinese. Clin Chem 2002;48:983-8.
  8. Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjöqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994;46:452-9.
  9. Lee SY, Sohn KM, Ryu JY, Yoon YR, Shin JG, Kim JW. Sequence-based CYP2D6 genotyping in the Korean population. Ther Drug Monit 2006;28:382-7.
  10. Arvanitidis K, Ragia G, Iordanidou M, Kyriaki S, Xanthi A, Tavridou A, Manolopoulos VG. Genetic polymorphisms of drug-metabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 in the Greek population. Fundam Clin Pharmacol 2007;21:419-26.
  11. Rideg O, Háber A, Botz L, Szücs F, Várnai R, Miseta A, Kovács GL. Pilot study for the characterization of pharmacogenetically relevant CYP2D6, CYP2C19 and ABCB1 gene polymorphisms in the Hungarian population. Cell Biochem Funct 2011;29:562-8.
  12. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 2005;5:6-13.

 

Source: http://www.fda.gov/Drugs.com

 

 

Perioperative Steroids Do Not Increase Serious Bleeding After Tonsillectomy .

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Children undergoing tonsillectomy who receive perioperative corticosteroid therapy — as recommended by current guidelines to reduce postoperative nausea and vomiting — do not face increased risk for postoperative bleeding, according to a JAMA study.

In response to a study suggesting such steroid use increases hemorrhage after tonsillectomy, researchers randomized some 300 children to perioperative intravenous dexamethasone or placebo. During the 14 days after tonsillectomy, rates of bleeding that required hospitalization or surgical repair (so-called level II or III bleeds) did not differ between the groups.

Level I bleeds — defined as any reported bleeding event, regardless of clinical evidence — were more common with dexamethasone than with placebo (11 vs. 7 events). However, the authors point out that such events tended to be “nondescript and self-limited.” Level II and III bleeds, they say, “are a more reliable indicator for complications.”

Source: JAMA