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IJC

International Journal of Cancer

Tonsillitis, tonsillectomy and Hodgkins lymphoma


Hanne Vestergaard, Tine Westergaard, Jan Wohlfahrt, Henrik Hjalgrim and Mads Melbye
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark

It has been debated whether the reported increased risk of Hodgkins lymphoma (HL) after tonsillectomy could be due to
some underlying factor rather than the surgery itself. We studied whether not only tonsillectomy but also tonsillitis was
associated with HL. This nationwide cohort study included all Danish residents during 19772001. Information on a diagnosis
of tonsillitis, tonsillectomy, or HL was obtained from national registries. During 124 million person-years we observed 2,988
HL patients of whom 58 were tonsillectomized (most with preceding tonsillitis) and 14 were diagnosed with only tonsillitis at
more than 1 year before HL diagnosis. Tonsillectomy was associated with a significantly increased HL risk in persons under
15 years of age as follows: 14 years after tonsillectomy, relative risk (RR) 5 3.9 [95% CI: 1.411; n 5 4]; >5 years after
tonsillectomy, RR 5 3.5 [1.48.5; n 5 5]. No young cases of HL occurred among persons diagnosed with only tonsillitis. In
contrast, 14 years after a hospital diagnosis of tonsillitis without subsequent tonsillectomy we found an increased HL risk in
persons aged 15 years or above as follows: 1534 years of age at HL diagnosis, RR 5 3.5 [1.67.7; n 5 6]; 351 years, RR 5
5.9 [2.216; n 5 4]. Age at tonsillitis or tonsillectomy did not modify HL risk within the 3 age strata. An increased HL risk
was found both after tonsillectomy and after an isolated diagnosis of tonsillitis. These results suggest that tonsillitis is a risk
factor for HL and not that, as previously reported, only the surgical removal of tonsils is a risk factor.

A prevailing hypothesis for an association between tonsillec- to study their potential effect on HL risk concomitantly as it
tomy and Hodgkins lymphoma (HL) has been that removal might be that tonsillitis rather than removal of the tonsils is
of the lymphoid tissue barrier would predispose to the de- associated with HL.
velopment of HL.1 However, so far, epidemiological studies In a national-wide cohort study we analyzed whether ton-
have been conicting,1,2 as casecontrol studies have reported sillectomy or hospital-diagnosed tonsillitis was associated
either an increased risk of HL following tonsillectomy1,36 or with an increased risk of HL. In addition, we also studied
no association.2,718 One nation-wide cohort study found a whether age at rst registration of tonsillectomy or tonsillitis
marginally increased risk for all age groups, but a 4-fold inuenced HL risk.
increased HL risk was found for persons tonsillectomized
before the age of 12 years.19 The latter nding is of particular Material and Methods
interest because the tonsils immunological functions are Study population
believed to decline from childhood to adulthood.20 However, We identied all Danish residents alive anytime between
few studies on tonsillectomy and HL have included age at

Epidemiology
1977 and 2001 in the Danish Civil Registration System (CRS)
tonsillectomy,6,7,18,19,21 leading to conicting results. as the study population. The CRS was established on April 1,
In many cases, tonsillectomy can be regarded as an indi- 1968, and since that date all persons living in Denmark have
cator of severe tonsillitis. Accordingly, in a population-based been assigned a personal identication number. The CRS
study we found that 81% of patients aged less than 20 years number allows identity secure linkage between registers, as
who had been tonsillectomized at a hospital had also been data in Danish registers were recorded by this number. Infor-
admitted for chronic tonsil disease within the previous mation in the CRS is regularly updated; data concerning per-
year.22 However, investigations studying the potential associa- sonal identication number, date of birth, sex, emigration
tion between tonsillitis and HL are sparse.2,8,13 As tonsillitis and vital status were extracted from the CRS.
most often precedes tonsillectomy, it is of particular interest Patients with tonsillectomy were identied in the Danish
National Patient Registry (NPR) and the Danish Health Secu-
Key words: epidemiology, Hodgkins lymphoma, risk factor, rity System, whereas patients with tonsillitis were only ascer-
tonsillitis, tonsillectomy tained from the NPR. The NPR includes registrations of the
DOI: 10.1002/ijc.24973 patients personal identication number, dates of hospital
History: Received 14 Aug 2009; Accepted 1 Oct 2009; Online 16 admission and discharge, discharge diagnoses and surgical
Oct 2009 operation codes registered according to the International
Correspondence to: Mads Melbye, Department of Epidemiology Classication of Diseases (ICD-8 and ICD-10). Reporting of
Research, Statens Serum Institut, Artillerivej 5, DK-2300 discharge diagnosis to the NPR has been mandatory since
Copenhagen, Denmark, Tel: 45-32-68-31-63, Fax: the start of the NPR on January 1, 1977. Since January 1,
45-32-68-31-65, E-mail: mme@ssi.dk 1995, outpatients tonsillectomized in hospital-based settings

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634 Tonsillitis, tonsillectomy and Hodgkins lymphoma

Table 1. Age-specic relative risk1 of Hodgkins lymphoma by history of tonsillitis and tonsillectomy during 19772001, Denmark
<15 years 1534 years 35 years
History of tonsillitis
3 3
and tonsillectomy N/Pyrs (310 ) RR (95% CI) 2
N/Pyrs (310 ) RR (95% CI) N/Pyrs (3103) RR (95% CI)
No tonsillectomy/no tonsillitis 97/22,640 1 reference 1,082/34,270 1 reference 1,720/64,300 1 reference
<1 year since rst tonsillitis or/and tonsillectomy
Tonsillectomy 0/73 (014.5) 4/76 2.0 (0.75.2) 10/12 35.7 (19.266.6)
Tonsillitis without tonsillectomy 0/40 (037.2) 1/20 1.8 (0.312.5) 2/8 10.1 (2.540.5)
14 years since rst tonsillitis or/and tonsillectomy
Tonsillectomy 4/236 3.9 (1.410.6) 12/310 1.4 (0.82.5) 2/53 1.6 (0.46.4)
Tonsillitis without tonsillectomy 0/117 (010.6) 6/59 3.5 (1.67.7) 4/27 5.9 (2.215.6)
5 years or more since rst tonsillitis or/and tonsillectomy
Tonsillectomy 5/182 3.5 (1.48.5) 29/866 1.2 (0.81.7) 6/281 1.0 (0.42.2)
Tonsillitis without tonsillectomy 0/112 (05.0) 4/180 0.8 (0.32.0) 0/72 (02.2)
1
RRs are adjusted for age, calendar period and sex.
2
Exact upper limits were calculated if no cases were observed.
Abbreviations: RR, relative risk; N, number of persons; Pyrs, person-years; CI, condence interval.

have also been registered. The following ICD codes were age-dependent disease entities constituting HLs bimodal age
used to identify acute tonsillitis: before 1994, ICD-8: 03400, curve.24,25 Adjustment was made for sex, age (5-year catego-
463; and from 1994 and later, ICD-10: DJ03. For chronic dis- ries) and calendar period (5-year intervals); all tests were
ease of the tonsils, the ICD-8 codes: 500.00, 500.02, 500.08, likelihood ratio tests. Exact upper limits for RR where no
500.09 and ICD-10: DJ35.0, DJ35.1, DJ35.3, DJ35.8, DJ35.9 cases were observed were estimated from the Poisson distri-
were selected. For tonsillectomy the operation codes were bution using expected number of cases calculated from age-,
2614, KEMB10 and KEMB20. We furthermore extracted data period- and sex-specic rates.
from the Danish Health Security System on tonsillectomies
performed in otolaryngology ofces during 19912001. For Results
the readability in this article, acute tonsillitis and chronic dis- Overall, the cohort members were followed for 124 million
ease of the tonsils are both referred to as tonsillitis if not oth- person-years. Tonsillitis and tonsillectomy patients were fol-
erwise specied. HL patients were identied in the Danish lowed for 0.64 million and 2.1 million person-years, respec-
Cancer Registry, which is considered virtually complete since tively. A total of 2,988 HL cases were observed. HL occurred
its establishment in 1943.23 HL cases were identied by ICD- in 89 persons with a history of tonsillitis (n 17) or tonsil-
7 code 201. lectomy (n 72). Among those with a history of tonsillec-
tomy, 72% had a prior hospital diagnosis of tonsillitis. The
Epidemiology

Statistical analysis mean follow-up time from tonsillitis and tonsillectomy to HL


The association between tonsillitis, tonsillectomy and HL was diagnosis was 4.1 and 7.0 years, respectively. A total of 72
analyzed by time since rst registration of tonsillectomy or patients were diagnosed with HL at more than 1 year after
tonsillitis and by age at rst tonsillitis or tonsillectomy regis- their rst registration of tonsillitis (n 14) or tonsillectomy
tration. This was evaluated by incidence rate ratios estimated (n 58). Their year of birth was distributed as follows: 17
by Poisson regression models. Incidence rate ratios were used were born before 1950, 5 during 195059, 27 during 1960
as a measure of relative risks (RRs). Follow-up began on Jan- 69, 31 during 197079 and 9 in 1980 or later, and their age
uary 1, 1977, or date of birth whichever came last and ended at HL ranged from 8 to 71 years.
on date of HL, death, emigration or December 31, 2001, Table 1 presents the age-specic RRs of HL according to
whichever came rst. The variables tonsillitis and tonsillec- history of tonsillectomy and tonsillitis at <1, 14 and 5
tomy were treated as time-dependent variables, i.e. persons years after the rst tonsillectomy or tonsillitis registration
registered with tonsillitis or tonsillectomy were followed as adjusted for age, calendar period and sex. The risk of HL was
exposed from time of tonsillitis or tonsillectomy. If a person signicantly increased among persons in the attained age
rst had a registration of tonsillitis and later was tonsillec- group of younger than 15 years for both 14 years (RR 3.9
tomized, the person was considered as unexposed from start [95% CI: 1.411]) and 5 years or more (RR 3.5 [1.48.5])
of follow-up until time of tonsillitis, as exposed to tonsillitis after the tonsillectomy, compared to persons in the same age
(i.e. tonsillitis without tonsillectomy) until time of tonsillec- group with history of neither tonsillectomy nor tonsillitis. In
tomy and then as exposed to tonsillectomy onwards. The contrast, there was no statistically signicant association
analyses were stratied according to attained age (<15, 15 between tonsillectomy and HL risk among persons aged 15
34 and 35 years) according to the hypothesized different 34 or 35 years. All HL patients who were younger than 15

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Vestergaard et al. 635

Table 2. Age-specic relative risk1 of Hodgkins lymphoma by age at rst tonsillitis or tonsillectomy registration
during 19772001, Denmark2
<15 years 1534 years 35 years
History of tonsillitis
and tonsillectomy N/Pyrs (3103) RR (95% CI)3 N/Pyrs (3103) RR (95% CI) N/Pyrs (3103) RR (95% CI)
No tonsillectomy/no tonsillitis 97/22,640 1 reference 1,082/34,270 1 reference 1,720/64,300 1 reference
Age at rst tonsillitis or tonsillectomy 09 years
Tonsillectomy 8/393 3.5 (1.77.3) 10/293 1.2 (0.62.3)
Tonsillitis without tonsillectomy 0/224 (03.5) 2/96 0.8 (0.23.0)
Age at rst tonsillitis or tonsillectomy 10 years
Tonsillectomy 1/25 4.8 (0.734.7) 31/883 1.2 (0.91.8) 8/333 1.1 (0.62.2)
Tonsillitis without tonsillectomy 0/6 (069.5) 8/143 1.8 (0.93.7) 4/100 1.7 (0.64.5)
1
RRs are adjusted for age, calendar period and sex.
2
First year of follow-up after tonsillectomy or tonsillitis is excluded from the analyses.
3
Exact upper limits were calculated if no cases were observed.
Abbreviations: RR, relative risk; N, number of persons; Pyrs, person-years; CI, condence interval.

years with diagnoses of tonsillitis had also been tonsillectom- was 1.1 [0.62.2, n 8] for persons tonsillectomized at the
ized. In contrast, HL risks were signicantly increased 14 age of 10 years or later. Only 2 cases had a diagnosis of ton-
years after tonsillitis, with RR estimates of 3.5 [1.67.7] and sillitis before the age of 10 years. They both occurred in the
5.9 [2.216] among persons aged 1534 and 35 years, attained age group of 1534 years and the corresponding RR
respectively. No such association with HL risk was found of HL was 0.8 [0.23.0]. Tonsillitis at age 10 years or more
among the age group of 5 years or more after tonsillitis. was found to be associated with an increased risk of HL (for
Less than 1 year after tonsillectomy or tonsillitis, HL risk the attained age group of 1534 years, RR was 1.8 [0.93.7,
was markedly increased among persons aged 35 years or n 8]; for 35 years or more, it was 1.7 [0.64.5, n 4]),
older, with RRs of 36 [1967] and 10 [2.541], respectively, compared to persons with no history of either tonsillitis or
compared to persons with no history of either tonsillectomy tonsillectomy.
or tonsillitis (Table 1). This suggested the possibility of Additional analyses including only patients with HL diag-
inverse causality, and consequently the rst year of follow-up nosed at 2 years or more after tonsillectomy or tonsillitis did
after tonsillectomy and tonsillitis was excluded in the follow- not alter risk estimates of HL materially (data not shown). A
ing analyses of age at rst tonsillectomy and rst tonsillitis further analysis including only tonsillectomies (n 58) and
registration and HL risk was adjusted for age, calendar period not tonsillitis did not alter the result of no association
and sex. between age at tonsillectomy and HL risk (data not shown).
Overall, persons with tonsillitis or tonsillectomy registered
before the age 10 years or at 10 years or later had relative Discussion

Epidemiology
HL risks of 1.40 [0.902.19] and 1.32 [1.001.74], respec- We found a signicantly increased risk of HL among persons
tively, compared to persons with no history of either tonsilli- in the attained age group of younger than 15 years with a
tis or tonsillectomy (data not shown). The ratio between the history of tonsillectomy, whereas persons aged 1534 and
RRs of the 2 groups is 1.40/1.32 1.07 [0.631.79], which 35 years had a signicantly increased HL risk of 14 years
changed to 1.40 [0.802.47] after further adjustment for type after tonsillitis. Age at tonsillitis or tonsillectomy within these
of disease (tonsillitis, tonsillectomy) and times since rst ton- 3 age strata did not modify the HL risk as previously
sillectomy or tonsillitis registration (14, 59 and 10 years). suggested.
Table 2 presents the age-specic RRs of HL by age at rst It has been questioned18,19 whether the increased risk of
tonsillitis or tonsillectomy registration before the age 10 years HL after tonsillectomy reported in several studies1,4,5 could
or at 10 years or older, compared to persons with no history be due to some underlying factor leading to tonsillectomy
of either tonsillitis or tonsillectomy. In the attained age group rather than the surgery itself. Our ndings support that this
of less than 15 years the RR of HL was 3.5 [1.77.3, n 8] could be the case; tonsillitis preceded most tonsillectomies.
and 4.8 [0.735, n 1], respectively, when tonsillectomy was As tonsillectomy did not further increase the HL risk after
registered before the age of 10 years or at 10 years or later. tonsillitis among persons aged 15 years or older, it would
Among persons aged 1534 years the corresponding RRs of seem reasonable to interpret that tonsillitis and not removal
HL when tonsillectomy was registered before or after the age of the tonsils was associated with the increased risk of HL, at
of 10 were 1.2 [0.62.3, n 10] and 1.2 [0.91.8, n 31], least in that age group. It should, however, be noted that all
respectively. Because of study design, persons aged 35 years cases aged less than 15 years with diagnoses of tonsillitis had
or older could not have been registered with tonsillitis or also been tonsillectomized. This could be due to small num-
tonsillectomy before the age of 10 years, and the RR of HL bers and, however, also be that tonsillitis associated with HL

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636 Tonsillitis, tonsillectomy and Hodgkins lymphoma

in children is more severe thus leading them to be tonsillec- reported a protective effect (RR 0.63 [95% CI: 0.460.86])
tomized more often than other children, whereas in adult- of tonsillectomy when performed before the age of 10 years
hood this is not the case. However, there remains speculation relying on self-reported data on age of tonsillectomy.21
as there are no available data that could be used to address The literature on a possible association between tonsillitis
this issue. Still, it cannot be excluded that our ndings repre- and HL is sparse. A casecontrol study including 60 male HL
sent different etiologies being involved in HL in persons aged patients13 as well as 2 other casecontrol studies of 53 HL
below and above 15 years. patients2 and 45 HL patients using classmates as controls8
Similar to our results, most of the studies on tonsillectomy did not nd any association with HL. None of the studies,
and attained age have found an increased HL risk among however, studied tonsillitis in relation to age at HL diagnosis.
younger persons. Among these, a Swedish population-based Furthermore, information on history of tonsillitis was self-
cohort study (including 20 HL patients) using registry infor- reported in 2 of the studies.2,13 To the best of our knowledge,
mation found HL risk among persons who were younger no prior studies have analyzed age at tonsillitis and HL risk.
than 20 years to be 3-fold [95% CI: 1.26.2] increased after The immunological role of the tonsils is believed to
tonsillectomy, while RRs were less and not statistically signi- decrease from childhood to adulthood. It has therefore been
cantly increased at older ages.19 An Italian study found a suggested that an altered or impaired immune response of
higher frequency of tonsillectomy among HL patients who the tonsils could constitute an etiological link between tonsil-
were younger than 40 years compared to HL patients who litis and HL. Epstein-Barr virus has been speculated to be a
were 40 years or older.12 Likewise, 2 American studies con- part of this explanation, as it has been associated with both
ducted by the same author in the same area and calendar pe- HL27 and tonsillitis.2830 However, so far no generally
riod reported an increased HL risk in children aged 12 years accepted etiological explanation exists on how tonsillitis may
or younger compared to their siblings6 and in persons aged contribute to the development of HL.
40 years or less,1 respectively. In contrast, 1 of 2 other Amer- The registration of tonsillectomy and tonsillitis in the
ican studies reported a lower tonsillectomy frequency in HL NPR started in 1977, making it more likely for patients aged
patients who were younger than 15 years compared to the less than 15 years to be followed from birth when compared
older age groups7 and the other study found only a signi- to the older age groups, who had their childhood before
cantly higher HL risk (RR 3.0 [95% CI: 1.36.9]) in per- 1977. Because most tonsillectomies and tonsillitis occur dur-
sons aged 55 years or older compared to their age-matched ing childhood it was thus less probable for the older age
siblings.26 The latter nding could, however, be due to lack groups to have their complete tonsil history registered during
of adjustment for calendar period as also suggested by the the study period. The risk of misclassication of history of
authors. tonsillectomy and tonsillitis was therefore higher in the older
The results from studies on age at tonsillectomy and HL age groups with long time since tonsillectomy or tonsillitis.
risk have varied.6,18,19,21 The previously mentioned Swedish Misclassication (outcome independent) may thus be a possi-
study found a 4-fold increased risk of HL if tonsillectomy bility in this age group, which may lead the risk estimates to-
was performed before the age of 12 years (n 7), but they ward no association. We have not validated the reliability
found no increased risk if tonsillectomy was performed at and completeness of the NPR and Health Security Systems
age of 12 years or later (n 13).19 However, this difference
Epidemiology

with respect to tonsillitis and tonsillectomy. However, studies


by age at tonsillectomy could to some degree be due to lack have described the validity of medical diagnoses to be high
of stratication by attained age as performed in our analyses. for uncomplicated diagnoses, and a particularly high agree-
The authors report that the cases with tonsillectomy per- ment for surgical procedures.31,32 We found no studies on
formed at age of 12 years or later had been diagnosed with the reliability or completeness of the Health Security Systems
HL at an older age than average. Furthermore, they reported Registry. This registry was established as an administrative
that the increased risk of HL after tonsillectomy is limited to registry in order to reimburse medical specialists from the
persons aged less than 20 years. Thus, the lower risk in per- National Health Insurance, which most likely makes it com-
sons with tonsillectomy performed at age of 12 years or later plete. In conclusion, misclassication is not considered a seri-
might be because they during follow-up on average are older ous problem because tonsillitis diagnoses do not require com-
and therefore have a lower risk.19 A recent German case plicated procedures and the surgical procedure tonsillectomy
control study comprising 115 HL patients and 710 controls is likely registered with a high validity and completeness.
with self-reported data on tonsillectomy reported a statisti- High socioeconomic status and educational level have been
cally insignicantly increased HL risk, when tonsillectomy suggested to confound the association between tonsillectomy
was performed before the age of 7 years.18 We did not nd and HL.15,21,26 This was, however, not conrmed in a Swedish
that age at tonsillitis or tonsillectomy modied the HL risk study.13 Furthermore, tonsillectomy and hospital-diagnosed
within age strata, which is similar to ndings in 2 American tonsillitis in Denmark is based on the entire population with
casecontrol studies including only tonsillectomy, where age- free access to healthcare and mandatory registration, making
matched siblings were used as controls.6,7 In contrast to all an association between socioeconomic status and registration
these results, a casecontrol study including 160 HL patients of tonsillitis or tonsillectomy unlikely. Nevertheless, an

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Vestergaard et al. 637

element of social confounding of the association between ton- In conclusion, tonsillectomy was associated with a signi-
sillectomy, tonsillitis and HL cannot be ruled out. cantly increased risk of HL among persons who were
Our study had several strengths. It was based on the younger than 15 years, whereas persons aged 15 years or
entire population of Denmark and used exposure information older had a signicantly increased HL risk at 14 years after
obtained from registries reported independently of and prior tonsillitis. As tonsillitis most often precedes tonsillectomy it
to HL development. Thus our data must be considered free cannot be ruled out that severe tonsillitis rather than removal
from selection bias and outcome-dependent misclassication. of the tonsils could be associated with increased HL risk.

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