Herpes zoster occurs frequently in immunocompromised patients, such as the elderly
and those with lymphoproliferative malignancies, AIDS, and in transplant recipients
(Dolin et al, 1978; Mazur and Dolin, 1978; Freidman-Kien et al, 1986; Melbye et al,
1987; Donahue et al, 1995; Poulsen et al, 1996; Gnann and Richard, 2002). An association
between cancer and herpes zoster has been recognised since 1955 (Wyburn-Mason, 1955),
and it has been hypothesised that herpes zoster may be a predictor of a subsequent
diagnosis of cancer (Smith and Fenske, 1995). Case reports have suggested such an
association (Wright and Winer, 1961; Muller, 1967; Cohen et al, 1984), but only three
relatively small studies have prospectively examined the risk of malignancy subsequent
to herpes zoster, and these found no significantly increased risk (Ragozzino et al,
1982; Fueyo and Lookingbill, 1984; Wurzel et al, 1986). Other studies have examined
this association, but most of them were based on patients with prevalent cancer, did
not include controls, or were unable to disentangle the temporal relationship (Wyburn-Mason,
1955; McGregor, 1957; de Moragas and Kierland, 1957; Wright and Winer, 1961; Merselis
et al, 1963; Muller, 1967; Rogers and Tindall, 1971; Schimpff et al, 1972; Brown,
1976). In addition, little is known about the prognosis of patients with cancer discovered
after hospitalisation with herpes zoster.
To assess the herpes zoster–cancer association without such limitations, we determined
the risk of cancer after hospitalisation for herpes zoster, as well as the prognosis
of such cancers, using nationwide population-based data from the Danish Registry of
Patients and the Danish Cancer Registry.
METHODS
The Danish National Registry of Patients was established in 1977, and 99.4% of all
discharges from Danish nonpsychiatric hospital departments are recorded there (Andersen
et al, 1999). Recorded information includes the civil registration number, the dates
of admission and discharge, the surgical procedures performed, and up to 20 discharge
diagnoses. The National Health Service provides tax-supported free medical care to
all Danish citizens. The civil registration number, which is unique to every Danish
citizen, permits accurate linkage of information among registers. Discharge diagnoses
were coded according to the Danish version of the International Classification of
Diseases, 8th revision (ICD-8), until 31 December 1993, and according to the 10th
revision thereafter (Andersen et al, 1999).
All hospitalisations for herpes zoster (ICD-8 codes 053.00–053.9 and ICD-10 codes
B02.0-B02.9) from 1 January 1977 to 31 December 1996 were extracted from the National
Registry of Patients. We identified 13 414 patients hospitalised with herpes zoster
and obtained their full hospitalisation history. This led to the exclusion of 402
patients who had received an organ transplantation before the diagnosis of herpes
zoster or were diagnosed with human immunodeficiency virus at any time during the
study period, and 2026 patients with a cancer diagnosis prior to or within 2 months
after the diagnosis of herpes zoster.
The remaining 10 986 herpes zoster patients were linked to the Central Population
Registry for verification of the civil registration number and for information on
vital status and emigration. This led to the exclusion of 398 patients who died during
the hospitalisation for herpes zoster or had an erroneous registration. The resulting
10 588 eligible herpes zoster patients were classified in two ways on the basis of
ICD codes: (1) into 7434 patients with uncomplicated herpes zoster and 3154 patients
with complicated herpes zoster; and (2) into 392 patients with disseminated herpes
zoster and 10 196 patients with localised herpes zoster.
The 10 588 herpes zoster patients were followed for cancer occurrence from 2 months
after the date of discharge with a first time diagnosis of herpes zoster to be certain
that the zoster diagnosis came before the cancer diagnosis until (1) the date of death
or emigration, identified through the Central Population Registry, (2) a diagnosis
of organ transplantation or primary immune deficiency, identified through the National
Registry of Patients, or (3) until 31 December 1998, whichever came first.
Information on cancer occurrence was obtained through record linkage to the Danish
Cancer Registry with records of all incident cases of cancer in Denmark since 1943.
Cancers are classified according to the modified Danish version of the International
Classification of Diseases, 7th revision (Storm et al, 1997). The registration is
based on notification forms that are completed by hospital departments (including
departments of pathology and forensic medicine) and practicing physicians whenever
a case of cancer is diagnosed or found at autopsy, and whenever changes to the initial
diagnosis are made. The cases thus reported manually are supplemented by cases revealed
by the computerised linkages to the death certificate file and the National Registry
of Patients. Ambiguous or contradictory information, either within a notification
form or between forms, leads to requests for clarification in approximately 10% of
notifications received. Comprehensive validation has shown that the Registry is 95–98%
complete and valid (Andersen et al, 1999).
Through the Cancer Registry, we aimed to identify a control group of up to 10 cancer
patients without herpes zoster for each herpes zoster patient with cancer. Controls
were matched on cancer type, gender, age in 10-year age groups, and calendar year
of diagnosis in 5-year periods. However, we were unable to identify 10 matching patients
for each herpes zoster patient with cancer, so the control group comprised only 12 193
patients.
Statistical analysis
The expected number of cancers was calculated on the basis of Danish national incidence
rates for primary cancers according to gender, age, and calendar time in 5-year intervals.
Multiplying the number of person-years under observation by the appropriate cancer
incidence rates yielded the number of cancers that would be expected if patients with
herpes zoster had the same risk of cancer as that of the general population. Confidence
intervals (CIs) for the standardised incidence ratio – that is, the relative risk,
calculated as the ratio of observed to expected cancers – were based on the assumption
that the observed number of cases in a specific category follows a Poisson distribution.
We examined the association between herpes zoster and all cancer types combined, as
well as the association between herpes zoster and haematological cancers, cancers
associated with immunosuppression (Nasca, 2001), and other cancers.
Through the Danish Cancer Registry, we obtained information on the extent of cancer
spread among the herpes zoster patients who developed cancer during follow-up (cases).
The extent of spread was divided into ‘no spread,’ ‘regional spread’, and ‘distant
metastases’. We calculated the prevalence ratio of distant metastases (the proportion
of cases with distant metastases divided by the proportion of controls with distant
metastases) and an associated 95% CI.
We used proportional hazards regression analyses to compare the risk of death after
a cancer diagnosis for cases relative to that for controls. We did separate analyses
on cases with haematological cancer and those with other types of cancer. The comparisons
were based on estimation of mortality ratios and associated 95% CI. All statistical
analyses were performed with Stata software (Stata Corporation, Texas, USA).
RESULTS
The 10 588 herpes zoster patients in the study (3972 men and 6616 women), were followed
for 75 774 person-years yielding an average length of follow-up of 7.2 years. The
median age at first hospitalisation for herpes zoster was 72 years.
Cancer risk
We found a total of 1427 cases of cancer with 1239 expected, yielding an overall relative
risk of 1.2. (95% CI 1.1–1.2). The relative risks were the same in men and women (data
not shown), and did not depend on the year of herpes zoster diagnosis (data not shown).
In the first year of follow-up, 188 cancers were identified, yielding a cumulative
cancer risk of 1.8%. Of the 188 cancers, 29 (15%) were haematological cancers, yielding
a cumulative risk of haematological cancer of 0.3%. The overall relative risk of a
diagnosis of cancer during the first year of follow-up was 1.3 (95% CI 1.1–1.5) and
did not vary with the year of hospitalisation. In the first year of follow-up, we
found a particularly high risk for haematological cancer with a relative risk of 3.4
(95% CI 2.3–4.9) (Table 1
Table 1
Relative risk (RR) for selected cancers within the first year of follow-up among patients
previously hospitalised for herpes zoster; follow-up started 2 months after the date
of discharge with herpes zoster
Observed
RR
95% CIa
All malignant neoplasms
188
1.3
1.1–1.5
Haematological cancers
29
3.4
2.3–4.9
Non-Hodgkin's lymphomab
11
3.8
1.9–6.7
Hodgkin's lymphoma
0
—
—
Multiple myeloma
8
4.8
2.1–9.4
Leukaemia
10
2.8
1.3–5.1
Immune-related cancers
32
1.1
0.8–1.6
Liver
3
1.5
0.4–6.0
Cervix
1
0.5
0.01–2.5
Nonmelanoma skin cancer
24
1.1
0.7–1.7
Malignant melanoma
1
0.5
0.01–2.5
Sarcomac
3
2.7
0.6–7.8
All other sites
d
127
1.2
1.0–1.4
Brain
0
—
—
Oesophagus
2
1.3
0.2–5.4
Stomach
6
1.1
0.4–2.3
Colon
12
0.8
0.4–1.4
Rectum
7
1.0
0.4–2.0
Pancreas
6
1.3
0.5–2.7
Lung
22
1.4
0.9–2.2
Breast
12
0.8
0.4–1.4
Corpus uteri
3
0.9
0.2–2.6
Ovary
7
2.3
0.9–4.8
Prostate
14
1.4
0.8–2.4
Kidney
6
1.7
0.6–3.8
Bladder
12
1.4
0.8–2.5
a
CI denotes confidence interval.
b
Non-Hodgkin's lymphoma is also classified as an immune-related cancer.
c
Among sarcomas, only Kaposi's sarcoma is regarded as an immune-related cancer.
d
Only selected sites are specified.
).
The relative risk of haematological cancer (Hodgkin's disease, non-Hodgkin's lymphoma,
multiple myeloma, and leukaemia) varied with time of follow-up after the herpes zoster
diagnosis (Tables 1 and 2
Table 2
Relative risk (RR) for selected cancers beyond the first year of follow-up among patients
previously hospitalised for herpes zoster; follow-up started 2 months after the date
of discharge with herpes zoster
Observed
RR
95% CIa
All malignant neoplasms
1239
1.1
1.1–1.2
Haematological cancers
111
1.7
1.4–2.0
Non-Hodgkin's lymphomab
38
1.6
1.1–2.2
Hodgkin's lymphoma
6
3.0
1.1–6.6
Multiple myeloma
22
1.7
1.1–2.6
Leukaemia
45
1.7
1.2–2.2
Immune-related cancers
251
1.1
1.0–1.2
Liver
13
1.3
0.7–2.2
Cervix
11
0.8
0.4–1.5
Nonmelanoma skin cancer
203
1.1
1.0–1.3
Malignant melanoma
15
0.8
0.5–1.3
Sarcomac
9
1.1
0.5–2.1
All other sites
d
877
1.1
1.0–1.2
Brain
29
1.6
1.1–2.3
Oesophagus
16
1.5
0.9–2.4
Stomach
44
1.3
0.9–1.7
Colon
97
0.9
0.7–1.1
Rectum
48
0.9
0.7–1.2
Pancreas
39
1.2
0.8–1.6
Lung
130
1.2
1.0–1.4
Breast
127
1.1
0.9–1.3
Corpus uteri
24
1.0
0.6–1.4
Ovary
23
1.1
0.7–1.6
Prostate
79
1.2
0.9–1.4
Kidney
32
1.3
0.9–1.8
Bladder
59
1.0
0.7–1.2
a
CI denotes confidence interval.
b
Non-Hodgkin's lymphoma is also classified as an immune-related cancer.
c
Among sarcomas, only Kaposi's sarcoma is regarded as an immune-related cancer.
d
Only selected sites are specified.
), so that it was 4.0 (95% CI 1.3–9.3) in the first 3 months, 3.2 (95% CI 1.4–6.4)
between 3 and 6 months, 4.6 (95% CI 2.3–8.2) between 6 and 9 months, 2.1 (95% CI 0.7–4.9)
between 9 months and 1 year, 1.9 (95% CI 1.5–2.5) between 1 and 5 years, 1.3 (95%
CI 0.9–1.9) between 5 and 10 years, and 1.7 (95% CI 1.1–2.6) after more than 10 years.
The relative risks of nonhaematological cancer in the same periods were 1.7 (95% CI
1.2–2.4), 1.5 (95% CI 1.1–1.9), 0.9 (95% CI 0.6–1.3), 0.8 (95% CI 0.5–1.1), 1.1 (95%
CI 1.0–1.2), 1.1 (95% CI 1.0–1.2), and 1.1 (95% CI 1.0–1.3), respectively.
For patients with uncomplicated herpes zoster, the relative risk of any cancer during
the first year of follow-up was 1.4 (95% CI 1.2–1.6), whereas it was 1.1 (95% CI 0.8–1.5)
for patients with complicated herpes zoster. For patients with disseminated herpes
zoster, it was 1.5 (95% CI 0.7–2.8), and it was 1.3 (95% CI 1.1–1.5) for patients
with other localised herpes zoster.
Cancer extent and prognosis
Because we were unable to identify matching patients for all 1382 herpes zoster patients
with cancer, only 1341 (97%) of these patients were included in the analyses of extent
of cancer and of survival after the cancer diagnosis. We had information on the extent
of cancer at the time of diagnosis in 79% of cases and 81% of controls. Among those
cases who developed cancer within the first year after hospitalisation for herpes
zoster, the prevalence ratio of distant spread was higher among the herpes zoster
patients than among the controls (prevalence ratio 1.27; 95% CI 0.99–1.63), whereas
it was close to unity among those who developed cancer more than 1 year after hospitalisation
for herpes zoster (prevalence ratio 1.07; 95% CI 0.92–1.23) (Table 3
Table 3
Extent of the spread of cancer according to the presence or absence of herpes zoster
Cancer <1 year after herpes zoster
Cancer 1–21 years after herpes zoster
Patients (N=176)
Controls (N=1623)
Prevalence ratio (95% CIa)
Patients (N=1165)
Controls (N=10 570)
Prevalence ratio (95% CIa)
Patients with data on spread
136 (77%)
1287 (79%)
923 (79%)
8531 (81%)
No spread
60 (44%)
607 (47%)
477 (52%)
4692 (55%)
Regional spread
29 (21%)
330 (26%)
226 (24%)
1914 (22%)
Distant metastasis
47 (35%)
350 (27%)
1.27 (0.99–1.63)
220 (24%)
1925 (23%)
1.07 (0.92–1.23)
a
CI denotes confidence interval.
).
The survival curves for herpes zoster patients in whom cancer was diagnosed within
the first year after herpes zoster hospitalisation, and their matched controls, were
almost similar with a mortality ratio of 1.02 (95% CI 0.85–1.22). For cases with haematological
cancer, however, the mortality ratio was 1.38 (95% CI 0.83–2.28), whereas that for
cases with nonhaematological cancer was 0.98 (95% CI 0.84–1.19) (Figure 1
Figure 1
Survival curves for patients with herpes zoster (solid lines) and haematological cancer
(black) or nonhaematological cancer (grey). Cancers were diagnosed within the first
year of follow-up. Follow-up started 2 months after the date of discharge with herpes
zoster. Matched controls are represented by dashed lines.
).
The survival curve for herpes zoster patients in whom cancer was diagnosed more than
1 year after the herpes zoster hospitalisation was similar to that for their matched
controls. The mortality ratio was 1.03 (95% CI 0.96–1.11). For cases with haematological
cancer, the survival curves for cases and their controls were only slightly different
with a mortality ratio of 1.11 (95% CI 0.85–1.46), and for cases with nonhaematological
cancer, the mortality ratio was 1.02 (95% CI 0.95–1.11).
DISCUSSION
In this large, population-based, follow-up study, we found an increased risk of several
types of cancer after hospitalisation for herpes zoster, particularly during the first
year of follow-up. In particular, there was a strong association between herpes zoster
and haematological cancers. Hospitalisation for herpes zoster was also a marker of
long-term cancer risk – even after 10 years, we found a 1.7-fold increase in the risk
of haematological cancer. Further, patients with herpes zoster were more likely to
have advanced cancer than matched controls, although survival curves for nonhaematological
cancer were similar. For haematological cancer, however, herpes zoster patients had
a poorer survival than their matched controls.
Our findings differ from those of the few previous studies on this topic (Ragozzino
et al, 1982; Fueyo and Lookingbill, 1984, Wurzel et al, 1986). In aggregate, three
small studies followed 662 patients. A total of 91 cancer cases were observed compared
with 84 expected in the two studies with internal or external controls (Ragozzino
et al, 1982; Fueyo and Lookingbill, 1984). No cancer cases were found in the third
study of children (Wurzel et al, 1986). Consequently, these studies had neither the
power to detect a substantially increased overall cancer risk nor the ability to study
site-specific cancer risks. In addition, they had few clinical details.
There may be several reasons as to why cancer might be associated with herpes zoster.
Increased diagnostic effort could explain the association in the short term, but it
seems unlikely for heightened surveillance to explain an increased risk many years
after the hospitalisation for herpes zoster. Moreover, there was no compensating deficit
after a time-limited period of increased risk, and the risk differed between haematological
and nonhaematological cancers.
Confounding by smoking may explain a part of the increased risk in the long term since
we found an increased risk of many tobacco-related cancers, and smoking, in itself,
has some impact on the immune function (Holt, 1987). One common risk factor for both
herpes zoster and cancer is cell-mediated immunity, which likely explains the strong
associations with haematological cancers. Varicella zoster virus remains in a dormant
state until the cell-mediated immune system is depressed and allows the virus to multiply.
There is some evidence that infections may promote certain types of cancers (Kuper
et al, 2000). It has also been suggested that herpes zoster has a direct carcinogenic
effect (Rogers and Tindall, 1971).
We found an increased long-term risk of brain tumour after herpes zoster hospitalisation,
but it is not possible to assess whether this finding was caused by chance or unknown
confounding, or whether it reflects the tropism for the virus towards neural tissue.
However, this hypothesis was not supported by the findings of an American case–control
study in which adults with glioma were less likely than controls to have had prior
varicella zoster virus infection or to have an immunoglobulin-G antibody response
adequate to indicate positivity (Wrensch et al, 1997; 2001).
The survival curves for herpes zoster patients with nonhaematological cancer and controls
were similar indicating that herpes zoster is not associated with particularly aggressive
nonhaematological cancer. For haematological cancer, on the other hand, herpes zoster
appears to be associated with more aggressive disease, and this is similar to what
has been found for other paraneoplastic syndromes, for example, venous thromboembolism
and hypercalcaemia (Kristensen et al, 1998; Sørensen et al, 2000).
The study population was large and well defined, and the long-term follow-up was complete,
since our design used computerised registries with complete nationwide coverage of
hospitalised patients. Consequently, our findings are limited to a population of severe
herpes zoster cases that require hospitalisation, but the risk estimates varied only
slightly with the type of herpes zoster patients. Limitations of our study are the
existence of coding errors and the possible misclassification of the herpes zoster
diagnosis in the National Registry of Patients. If nondifferential, this problem would
reduce the strength of the associations we reported. Also, we lacked direct information
on potential confounders, such as cigarette smoking and use of immunosuppressive drugs.
Our data clearly showed an association between hospitalisation for herpes zoster and
cancer, in contrast to previous research, and even demonstrated a long-term association.
Our data are consistent with the hypothesis that herpes zoster may be a marker of
haematological cancers, in particular. Nonetheless, the limitations of our data prevent
us from suggesting guidelines for searching for occult cancer in patients with herpes
zoster. In our cohort, patients diagnosed with cancer in the first 2 months after
herpes zoster were excluded, but it is most likely that some cancers diagnosed in
the following months were present at the time of hospitalisation for herpes zoster.
Early diagnosis of some cancers would have required extensive work-up, and it is unclear
whether early diagnosis would have changed the outcome. Some of the haematological
cancers might be detected by simple methods, but only 1.8% of herpes zoster patients
had a cancer diagnosis within the first year of follow-up, including 0.3% with haematological
cancer, and 35% had metastases at the time of diagnosis. These findings suggest that
cancer screening of patients hospitalised for herpes zoster will have low efficacy.