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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

The relationship between psoriasis and increased cancer risk is debated.

The aim of this study was to evaluate if there is an increase in the background risk of cancer in psoriasis patients compared with the general population.

A systematic literature search was performed on PubMed, Embase and Cochrane databases, using the keywords ‘Psoriasis [Majr] AND Neoplasms’, from 1980 to January 2012. Meta-analysis was performed based on observational studies showing consistency in cancer risk assessment methods.

Of the 1080 articles retrieved, 37 references were selected. There may be an increased risk of some solid cancers in psoriasis: respiratory tract cancer [standardized incidence ratio (SIR) = 1.52, 95% confidence interval (CI) 1.35–1.71], upper aerodigestive tract cancer (SIR = 3.05, 95% CI 1.74–5.32), urinary tract cancer (SIR = 1.31, 95% CI 1.11–1.55) and liver cancer (SIR = 1.90, 95% CI 1.48–2.44). The risk of non-Hodgkin lymphoma appears slightly increased in psoriasis (SIR = 1.40, 95% CI 1.06–1.86). Psoriasis patients have an increased risk of squamous cell carcinoma (SIR = 5.3, 95% CI 2.63–10.71) and basal cell carcinoma (SIR = 2.00, 95% CI 1.83–2.20), whereas the risk of melanoma is not increased.

There was a large heterogeneity in studies assessing cancer risk in psoriasis preventing from including all studies in meta-analysis.

This systematic literature review shows a small increased risk of some solid cancers in psoriasis, especially those linked to alcohol drinking and cigarette smoking. A higher risk of non-melanoma skin cancers, especially squamous cell carcinoma, is shown, mainly due to previous exposure to 8-methoxypsoralen-ultraviolet-A (PUVA), ciclosporin and possibly methotrexate.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Psoriasis is a chronic inflammatory disease of the skin and joints that affects 3–4% of the population worldwide.[1] It has been suggested that patients with chronic inflammatory diseases such as rheumatoid arthritis,[2, 3] Crohn's disease[4, 5] or psoriasis might be at increased risk of cancer. This was hypothesized to be related to impaired immunosurveillance resulting from the effect of chronic inflammation[6-8] and immunosuppressive pharmacological agents. The potential role of comorbidities such as cigarette smoking and alcohol consumption has to be taken into account when considering cancer risk in psoriasis. Previous exposure to systemic treatment including immunosuppressive drugs, methotrexate, ciclosporin and ultraviolet (UV) radiation must also be considered.

The present systematic literature review (SLR) was undertaken to prepare for evidence-based recommendations on the evaluation of cancer risk in psoriasis. The reviewing process leading to these recommendations is described in detail in the same issue of this journal.[9] This SLR aimed at answering the following questions:

Is there an increased risk of some cancers in psoriasis patients compared with the general population? If yes, can this risk be linked to: (a) comorbidities such as smoking and alcohol? (b) the disease itself? (c) treatments received for psoriasis?

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Systematic literature search

We performed a systematic review of all epidemiological studies investigating the risk of cancer in adult psoriasis patients published between 1980 and January 2012. The Cochrane, PubMed and Embase databases were systematically searched. The research used the following combination of Medical Subject Headings (MeSH): ‘Psoriasis (Majr) AND Neoplasms’. We limited the literature search to articles on humans over 19 years of age, written in English or French, and reporting original data.

We used the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and NEWCASTLE-OTTAWA items to evaluate the quality of studies and excluded studies with lower quality.[10, 11]

Given the lack of long-term epidemiological studies investigating cancer risk with biologicals in psoriasis, the risk of cancer attributable to biologicals could not be carefully assessed and clinical studies with biological agents were not included in the analysis.

Data extraction and analysis

For all the articles, we extracted the following data: type of database, author, year of publication, study design, number of psoriasis patients, number and origin of controls (i.e. general population or dermatology patients), follow-up period, type of cancer: cutaneous [malignant melanoma and non-melanoma skin cancer (NMSC)], haematological cancers (overall lymphomas and subtypes when specified, leukaemias), solid cancers (overall and by organ). Whenever possible, we collected data about: (a) comorbidities (cigarette smoking, alcohol drinking); (b) previous treatment received for psoriasis: type, duration and dose; (c) disease severity.

Two reviewers (Ch.P, CP) independently performed the systematic electronic searches and data extraction. Disagreements were resolved by discussion, and reviewers were 100% unanimous in their final decisions.

In each selected study, the effect size criteria and its confidence interval were searched. Several estimators were identified: odds-ratio (OR) for case–control studies or cross-sectional studies, relative risk (RR), standardized incidence ratio (SIR) or incidence rate ratio (IRR) for the cohort studies. Meta-analysis was performed only on homogeneous studies according to their estimators, to minimize the heterogeneity.

To compute data issued from the several studies selected, we used the generic inverse variance approach. Estimates and their standard errors could be entered directly, but the data should be entered as natural logarithms (e.g. as a log OR and the standard error of the log OR). The software undertook fixed-effect meta-analysis and random-effects (Der Simonian and Laird) meta-analysis, along with assessments of heterogeneity. This method provides with a common risk estimate with a 95% confidence interval (CI), taking into account the weight of the different studies. Risk estimators and theirs 95% CI were shown on forest plots for each type of cancer studied. Statistical heterogeneity of studies considered was assessed on the basis of the Q-test (χ2), using a significance level of 0.05, and reported the I2 statistic, in which high values indicate high heterogeneity.

All computations were performed using Revman 5.1.6 software package developed by the Nordic Cochrane Centre [Review Manager (RevMan) (Computer program). Version 5.1; The Cochrane Collaboration, 2011, The Nordic Cochrane Centre, Copenhagen]. P-values less than 0.05 were considered significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

From an initial selection of 1080 references: 1013 were excluded after reading the title or the abstract, 32 after reading the article. Two articles were retrieved by handsearching references lists from selected articles. Finally 37 references were retained. The detailed flowchart summarizing the selection process is displayed in Fig. 1.

image

Figure 1. Flowchart of study selection process.

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Overall cancer risk excluding NMSC

Eleven studies were selected (Table 1).[12-22] A significant association between overall cancer risk and psoriasis was found in five studies with various designs.[12, 14, 16, 19, 20] Four of them were population-based studies[12, 16, 19, 20] and one included hospitalized patients.[14] Six studies could be included in a meta-analysis based on the analysis of methodological quality and consistency in risk analysis[13-15, 17, 18, 21] with an overall SIR (95% CI) of cancer of 1.16 (95% CI 1.07–1.25) (Fig. 2). The only study including patients with psoriatic arthritis did not find any increased risk of cancer in psoriatic arthritis compared with the general population.[21] Among the five studies not included in the meta-analysis, four population-based studies also showed a significant increased risk of cancer in psoriasis,[12, 16, 19, 20] whereas one retrospective case–control study did not show any increased risk of cancer in psoriasis.[22]

Table 1. Studies selected estimating the overall risk of cancer excluding non-melanoma skin cancers (NMSC) in psoriasis
Author, study designNumber of patients, type, treatment exposureControlsMean follow-up (years)Main results (95% CI)
  1. a

    Included in the meta-analysis.

  2. G, general population; H, hospital; HR, hazard ratio; IRR, incidence rate ratio; IS, immunosuppressive drugs; MTX, methotrexate; ns, non-significant; OP, outpatients; PUVA, 8-methoxypsoralen-ultraviolet-A; RR, relative risk; SIR, standardized incidence ratio; vs., versus.

Prizment et al.,[12] case–control719 OP, women > 65 years old32 191 G15

HR = 1.2 (1.0–1.4)

after adjustment for smoking

HR = 1.1 (0.9–1.4)

Paul et al.,[13] prospective cohort1252 H, ciclosporinG4.5SIR = 1.3 (0.8–1.9)a
Frentz et al.,[14] prospective cohort6905 HG9.3SIR = 1.23 (1.11–1.36)a
Hannuksela et al.,[15] prospective cohort158 H, bath-PUVAG7.6SIR = 1.3 (0.5–2.8) a
Margolis et al.,[16] retrospective cohort17 620 OP234 304 OP2.5RR = (excluding lymphoproliferative malignancies)

Patients treated with systemic therapy

RR = 1.46 (1.04–2.05)

Patients never treated with systemic therapy

RR = 1.0 (0.90–1.12)

Stern et al.,[17] prospective cohort984 H PUVAG20RR = 1.08 (0.93–1.24)a
Hannuksela et al.,[18] prospective cohort944 H bath-PUVAG14.7SIR = 1.1 (0.8–1.4)a
Brauchli et al.,[19] observational study + nested case–control33 760 OP34 001 G4.6IRR = 1.13 (1.02–1.24)
Chen et al.,[20] retrospective cohort3686 OP, Taiwanese 530 (14%) received oral treatment200 000 G5.6

HR = 1.66 (1.38–2.00)

Phototherapy or systemic treatments vs. topicals: HR = 1.09 (0.74–1.63)

Rohekar et al.,[21] prospective cohort665 H, psoriatic arthritis (>50% received MTX or IS)G26RR = 0.98 (0.77–1.24)a
Bhate et al.,[22] retrospective case–control2247 OP4494 OP56 vs. 90 = ns
image

Figure 2. Overall risk of cancer excluding NMSC in psoriasis: meta-analysis.

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Risk of solid cancers by organ class

Respiratory tract

Fourteen studies were selected (Table 2).[12-14, 17-27] Six studies showed a significant association between lung cancer and psoriasis. Among them were three prospective cohort studies including hospitalized patients,[14, 23, 24] one large population-based case–control study including adjustment of estimates according to some comorbidities (smoking),[12] one Taiwanese retrospective cohort finding a higher cancer risk in male patients only[20] and a retrospective cohort study of lower strength.[27] In only two studies, the estimates were adjusted for smoking.[12, 19] We performed a meta-analysis including seven studies[13, 14, 17, 18, 21, 23, 24]: the overall SIR was 1.52 (95% CI 1.35–1.71) (Fig. 3).

Table 2. Studies selected estimating the risk of respiratory tract cancer in psoriasis
Author, study designNumber of patients, type, treatment exposureControlsMean follow-up (years)Main results (95% CI)
  1. a

    Included in the meta-analysis.

  2. G, general population; H, hospital; HR, hazard ratio; IRR, incidence rate ratio; IS, immunosuppressive drugs; MTX, methotrexate; ns, non-significant; o/e, observed/expected; OP, outpatients; PUVA, 8-methoxypsoralen-ultraviolet-A; RR, relative risk; SIR, standardized incidence ratio; UV, ultraviolet; vs., versus.

Prizment et al.,[12] case–control719 OP, women > 65 years old32 191 G15

HR = 1.9 (1.2–3.0)

after adjustment for smoking HR = 1.3 (0.8–2.0)

Rohekar et al.,[21] prospective cohort665 H, psoriatic arthritis (>50% received MTX or IS)G26SIR = 0.88 (0.46–1.69)a
Paul et al.,[13] prospective cohort1252 H, ciclosporinG4.5SIR = 0.6 (0.1–2.2)a
Frentz et al.,[14] prospective cohort6905 HG9.3SIR = 1.5 (1.3–1.9)a
Hannuksela et al.,[23] prospective cohort5687 HG14SIR = 1.5 (1.2–1.8)a
Ji et al.,[24] prospective cohort15 858 HG10SIR = 1.78 (1.51–2.09)a
Stern et al.,[17] prospective cohort984 H PUVAG20RR = 1.05 (0.74–1.44)a
Hannuksela et al.,[18] prospective cohort944 H bath-PUVAG14.7SIR = 1 (0.4–2.0)a
Brauchli et al.,[19] observational study+ nested case–control33 760 OP, 50% of patients <50 years old34 001 G4.6IRR = (adjustment for smoking) 0.79 (0.6–1.06)
Chen et al.,[20] retrospective cohort3686 OP, Taiwanese, 530 (14%) received oral treatment200 000 G5.6

HR = 1.46 (0.85–2.49)

In men HR = 1.92 (1.12–3.29)

Tsai et al.,[25] case–control

51 800 OP, Taiwan

9265 (18%) received UV or systemic treatment

207 200 GRR = 0.68 (0.54–0.85)
Lindelof et al.,[26] retrospective cohort20 328 OPG

Men o/e = 5/8.3

Women o/e = 3/2.8: ns

Bhate et al.,[22] retrospective case–control2247 OP4494 OP5 cases/4 controls: ns
Lindegard et al.,[27] retrospective cohort372 HG10o/e = 34 in women, P < 0.0001
image

Figure 3. Risk of respiratory tract cancer in psoriasis: meta-analysis.

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Upper aerodigestive tract

Eight studies were selected (Table 3).[13, 14, 18-20, 23-25] Five prospective cohort studies including hospitalized psoriasis patients could be included in a meta-analysis:[13, 14, 18, 23, 24] the overall SIR was 3.05 (95% CI 1.74–5.32) (Fig. 4). Among the three studies not included in the meta-analysis, two Taiwanese population-based studies also found a significant association.[20, 25] In the only study where adjustments were made regarding smoking and alcohol consumption, no significant association was found.[19] However in this population-based study, nearly 50% of patients were under the age of 50 and the follow-up period was short (4.6 years).

Table 3. Studies selected estimating the risk of upper aerodigestive tract cancer in psoriasis
Author, study designNumber of patients, type, treatment exposureControlsMean follow-up (years)Main results (95% CI)
  1. a

    Included in the meta-analysis.

  2. G, general population; H, hospital; HR, hazard ratio; IRR, incidence rate ratio; ns, non-significant; OP, outpatients; PUVA, 8-methoxypsoralen-ultraviolet-A; RR, relative risk; SIR, standardized incidence ratio; UADT, upper aerodigestive tract; UV, ultraviolet.

Paul et al.,[13] prospective cohort1252 H, ciclosporinG4.5Oesophagus SIR = 5.1 (0.6–18.4)a
Frentz et al.,[14] prospective cohort6905 HG9.3

Pharynx SIR = 2.9 (1.3–5.8)a

Larynx SIR = 2.0 (1.0–3.6)

Oral cavity SIR = 1.7 (1.0–2.7)

Hannuksela et al.,[23] prospective cohort5687 HG14

Pharynx SIR = 1.3 (0.3–3.9)

Oesophagus SIR = 1.2 (0.5–2.5)

Larynx SIR = 2.9 (1.5–5.0)a

Ji et al.,[24] prospective cohort15 858 HG10

UADT SIR = 1.97 (1.46–2.62)

Oesophagus SIR = 2.97 (1.97–4.30)a

Hannuksela et al.,[18] prospective cohort944 H bath-PUVAG14.7Oesophagus SIR = 3.2 (0.4–12)a
Brauchli et al.,[19] observational study + nested case–control

33 760 OP,

50% of patients <50 years old

34 001 G4.6Oesophagus IRR = (adjustment for alcohol and smoking) 1.36 (0.72–2.54)
Chen et al.,[20] retrospective cohort

3686 OP, Taiwanese,

530 (14%) received oral treatment

200 000 G45.6Oropharynx larynx HR = 2.16 (1.17–3.96)
Tsai et al.,[25] case–control

51 800 OP, Taiwanese;

9265 (18%) received UV or systemic treatment

207 200 GLip, oral cavity and pharynx RR = 1.49 (1.22–1.80)
image

Figure 4. Risk of upper aerodigestive tract cancer in psoriasis: meta-analysis.

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Bladder/kidney/urinary tract

Ten studies were selected (Table 4).[14, 17-20, 22-26] Five prospective cohort studies including hospitalized psoriasis patients could be included in a meta-analysis.[14, 17, 18, 23, 24] The overall SIR was 1.31 (95% CI 1.11–1.55) (Fig. 5). Among the five studies not included in the meta-analysis, a significant association was also found in two population-based retrospective cohorts.[20, 26] In the only study where adjustments were made regarding smoking consumption, no significant association was found between psoriasis and kidney or bladder cancers.[19]

Table 4. Studies selected estimating the risk of urinary tract cancer in psoriasis
Author, study designNumber of patients, type, treatment exposureControlsMean follow-up (years)Main results (95% CI)
  1. a

    Included in the meta-analysis.

  2. G, general population; H, hospital; HR, hazard ratio; IRR, incidence rate ratio; ns, non-significant; OP, outpatients; PUVA, 8-methoxypsoralen-ultraviolet-A; RR, relative risk; SIR, standardized incidence ratio.

Frentz et al.,[14] prospective cohort6905 HG9.3Bladder SIR = 1.0 (0.7–1.4) a
Ji et al.,[24] prospective cohort15 858 HG10Bladder SIR = 1.51 (1.2–1.88) a
Stern et al.,[17] prospective cohort984 H PUVAG20Urinary tract RR = 1.17 (0.69–1.85) a
Hannuksela et al.,[18] prospective cohort944 H bath-PUVAG14.7

Kidney SIR = 2.9 (1.1–6.3)

Bladder SIR = 1.1 (0.2–3.2) a

Brauchli et al.,[19] observational study + nested case–control33 760 OP34 001 G4.6Kidney bladder IRR = (adjustment for smoking) 1.25 (0.84–1.85)
Chen et al.,[20] retrospective cohort3686 OP, Taiwanese200 000 G5.6Urinary tract HR = 3.18 (1.54–6.57)
Hannuksela et al.,[23] prospective cohort5687 HG14Bladder-urethral SIR = 1.4 (0.9–2.1) a
Lindelof et al.,[26] retrospective cohort20 328 OPGKidney 1.4 (0.9–2.1), in women RR = 2.79 (1.6–4.5)
Tsai et al.,[25] case–control51 800 OP, Taiwanese207 200 GGenito-urinary tract RR = 1.00 (0.87–1.15)
Bhate et al.,[22] retrospective case–control2247 OP4494 OP6 cases/12 controls: ns
image

Figure 5. Risk of urinary tract cancer in psoriasis: meta-analysis.

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Digestive tract/liver/pancreas

Eight studies were selected.[18-20, 22-26] Regarding liver cancer, three prospective cohort studies including hospitalized psoriasis patients were included in a meta-analysis.[18, 23, 24] The overall SIR was 1.90 (95% CI 1.48–2.44). For pancreatic cancer, the meta-analysis included two prospective cohort studies in hospitalized psoriasis patients:[23, 24] the overall SIR was 1.46 (95% CI 1.10–1.95). Among the studies that could not be included in the meta-analysis, three studies showed a significant association between psoriasis and cancers of the digestive tract:[19, 20, 25] Chen et al.[20] found an increased risk of digestive, liver and gallbladder cancers [age- and sex-adjusted hazard ratio (HR) = 2.02, 95% CI 1.33–3.07] in 3686 Taiwanese psoriasis outpatients retrospectively compared to 200 000 controls from the Taiwanese general population. Tsai et al.[25] found a higher prevalence of digestive cancer in 51 800 Taiwanese psoriasis outpatients compared to matched controls from the general population (RR = 1.57, 95% CI 1.41–1.74). In a large population-based study with a nested case–control analysis, Brauchli et al.[19] found an increased risk of digestive cancer in 33 760 psoriasis outpatients compared to 340 001 matched psoriasis-free patients (IRR = 2.20, 95% CI 1.18–4.09). Two retrospective studies of lower strength found no significant association.[22, 26]

Breast

Twelve studies were selected.[12-14, 17-19, 21-24, 26, 39] Seven prospective cohort studies including hospitalized psoriasis patients could be included in a meta-analysis.[13, 14, 17, 18, 21, 23, 24] The overall SIR was 1.15 (95% CI 1.02–1.29). Among the five other studies, two showed a significant association.[26, 39]

Colorectal

Ten studies were selected.[12-14, 18-20, 23, 24, 26, 39] Five prospective cohort studies including hospitalized psoriasis patients were included in a meta-analysis:[13, 14, 18, 23, 24] the overall SIR was not significantly increased (1.12, 95% CI 0.95–1.32). Among the five remaining studies, two population-based studies[12, 20] found a significant association, whereas two others found no significant association[19, 26] and one large prospective cohort study of psoriasis patients exposed to 8-methoxypsoralen-ultraviolet-A (PUVA) therapy[39] found a significant association for colon cancer, but not for rectal cancer.

Central nervous system

Five studies[17, 18, 23, 24, 26] were selected and included in a meta-analysis: the overall SIR was not significantly increased in psoriasis (SIR = 1.24, 95% CI 0.98–1.59).

Cervix

Three studies were selected.[22, 24, 26] None of them found a significantly increased risk in psoriasis.

Risk of haematologic cancers

‘Haematologic cancers’ or ‘lymphomatopoietic malignancies’ (unspecified)

Four studies[20, 21, 25, 39] were selected: one prospective cohort study including hospitalized patients with psoriatic arthritis,[21] one prospective cohort study including psoriasis patients exposed to PUVA[39] and two Taiwanese population-based studies.[20, 25] Only Tsai et al.[25] found a significant higher risk of cancer of ‘lymphatic and hematopoietic tissue’ in 51 800 Taiwanese psoriasis outpatients compared to matched controls from the general population, with a RR of 1.62 (95% CI 1.21–2.16). In this study, 18% (n = 9265) of the patients had received UV or systemic treatment.

Overall lymphoma

Seven studies were selected.[13, 16, 17, 19, 22, 28, 29] Three studies found an increased risk of lymphoma in psoriasis[16, 19, 29] with HR or RR varying from HR = 1.35 (95% CI 1.17–1.55) to RR = 7.95 (95% CI 4.94–12.79). No increased risk of lymphoma was detected in the remaining four studies (Table 5).[13, 17, 22, 28]

Table 5. Studies selected estimating the risk of lymphoma overall in psoriasis
Author, study designNumber of patients, type, treatment exposureControlsMean follow-up (years)Main results (95% CI)
  1. CTCL, cutaneous T-cell lymphomas; G, general population; H, hospital; HL, Hodgkin lymphomas; HR, hazard ratio; IRR, incidence rate ratio; MTX, methotrexate; NHL, non-Hodgkin lymphomas; ns, non-significant; OP, outpatients; PUVA, 8-methoxypsoralen-ultraviolet-A; RR, relative risk; SIR, standardized incidence ratio.

Stern et al.,[28] prospective cohort526 H, PUVAG30

IRR = (NHL and HL), CTCL excluded = 0.85 (0.37–1.67)

MTX > 36 months: multivariate IRR = 3.65 (1.34–9.90)

Paul et al.,[13] prospective cohort1252 H, ciclosporinG4,5Lymphomas: SIR = 2 (0.2–7.2)
Margolis et al.,[16] retrospective cohort

17 620 OP,

1101 (6.2%) received systemic treatment (MTX 50%, ciclosporin 3.7%)

234 304 OP with hypertension2,5

Systemic treatment: RR = 7.95 (4.94–12.79)

No systemic treatment: RR = 2.11 (1.63–2.74)

Stern et al.,[17] prospective cohort984 H PUVAG20Lymphomas: RR = 0.88 (0.32–1.92)
Brauchli et al.,[19] observational study + nested case–control

33 760 OP

(MTX 1.6%, ciclosporin 0.2%)

34 001 G4,6

Total lymphomas: IRR = 1.76 (1.19–2.58)

CTLT excluded: IRR = 1.55 (1.03–2.31)

Nested case–controls: highest risk if oral treatment: OR 10.17 (3.24–31.94)

Gelfand et al.,[29] retrospective cohort

153 197 OP

3994 (2.5%) received systemic treatment (MTX 58%, ciclosporin 10%)

765 950 OP4,5

All patients: HR = 1.35 (1.17–1.55)

Systemic treatment: HR = 1.59 (0.88–2.89)

No systemic treatment: HR = 1.34 (1.16–1.54)

Bhate et al.,[22] retrospective case–control2247 OP4494 OP age- and sex-matched2 cases/3 controls: ns
Non-Hodgkin lymphoma

Six studies were selected.[14, 18, 23, 24, 26, 29] The meta-analysis included four studies.[14, 18, 23, 24] The overall SIR was significantly increased in psoriasis: SIR = 1.40 (95% CI 1.06–1.86) (Fig. 6). Among the two studies not included in the meta-analysis, the retrospective population-based cohort study published by Gelfand et al.[29] found no increased risk of Non-Hodgkin lymphoma (NHL) in psoriasis patients – after excluding cutaneous T-cell lymphoma (CTCL) – HR = 1.14 (95% CI 0.96–1.35). The results held true in the severe psoriasis group of patients treated with systemic agents. No increased risk of lymphoma was observed in a Scandinavian retrospective cohort.[26]

image

Figure 6. Risk of non-Hodgkin lymphoma in psoriasis: meta-analysis.

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Hodgkin lymphoma

Four studies were selected.[18, 23, 24, 29] Hannuksela et al.[23] found an increased risk of Hodgkin lymphoma (HL) in a cohort of 5687 Finnish hospitalized patients followed-up for 14 years (SIR = 3.3, 95% CI 1.4–6.4). The role of prior oral anti-psoriasis medications on the development of HL was not specifically studied. Gelfand et al.[29] found an increased risk of HL (age- and sex-adjusted) in psoriasis both in patients receiving systemic therapies (HR = 3.18, 95% CI 1.01–9.97) and in those who did not (HR = 1.42, 95% CI 1.00–2.02). No increased risk of HL was observed in a Scandinavian retrospective cohort.[26]

Leukaemia

Six studies were selected.[13, 14, 17, 19, 24, 26] A significantly increased risk of leukaemia (SIR = 7.3, 95% CI 1.5–21.5) was observed in a cohort of psoriasis patients treated with ciclosporin.[13] Brauchli et al.[19] also found an increased risk of leukaemia (IRR = 1.89, 95% CI 1.21–2.94) in psoriasis. In four other studies,[14, 17, 24, 26] no increased risk of leukaemia was observed. We performed a meta-analysis including four studies,[13, 14, 17, 24] the overall SIR was not significantly increased. However, a high level of heterogeneity was observed (Fig. 7).

image

Figure 7. Risk of leukaemia in psoriasis: meta-analysis.

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Cutaneous lymphoma

Two studies specifically assessed the risk of skin lymphoma in psoriasis: Frentz et al.[14] found a highly increased risk of mycosis fungoïdes (SIR = 15.1, 95% CI 4.1–38) in a cohort of 6910 Danish psoriasis patients followed-up for 9.3 years. However, this excess risk was almost exclusively observed during the first year of follow-up, highly suggesting a diagnostic confusion between psoriasis and mycosis fungoïdes in some patients. Gelfand et al.[29] also found an increased risk of CTCL associated with psoriasis (HR = 4.34, 95% CI 2.89–6.52).This increased risk of CTCL was particularly high in patients with severe psoriasis (HR = 10.75, 95% CI 3.89–29.76). This latter study used an administrative general practitioner database, and misclassification between psoriasis and CTCL may here again explain the strong association between psoriasis and CTCL.

Risk of skin cancers

Melanoma

Fourteen studies were selected. Only three showed an increased risk in psoriasis.[20, 32, 43] Stern et al.[32] reported an increased risk of melanoma in psoriasis patients treated with PUVA therapy: about 15 years after the first treatment with PUVA, there was a significantly higher risk of melanoma in the study patients compared with age- and gender-matched US population (RR = 2.3, 95% CI 1.1–4.1). The risk was higher among patients who received at least 250 PUVA treatments compared to those who received less than 250 PUVA treatments (RR = 3.1, 95% CI 0.9–10.5).[32] In the most recent report,[43] the age- and sex-adjusted IRR of all melanomas was 2.9 (95% CI 1.3–6.4) in patients exposed to more than 200 PUVA treatments compared with those exposed to lower doses. The risk appeared to be increased (IRR = 5.9, 95% CI 2.2–15.9) when the time since the first treatment was above 15 years vs. under 15 years. In a population-based cohort study in Taiwan, Chen et al.[20] found an increased risk of melanoma among 3686 psoriasis patients compared to 200 000 randomly selected psoriasis-free patients (sex- and age-adjusted HR = 3.10, 95% CI 1.24–7.71). Psoriasis patients who received either phototherapy or systemic treatments did not show any significantly elevated risk of overall cancer (including melanoma) compared with those who received only topical agents (sex- and age-adjusted HR = 1.09, 95% CI 0.74–1.63). Conversely, there was no increased risk of melanoma in two European cohorts of PUVA-treated patients.[30, 31] There was no excess of melanoma in two cohorts of patients treated with 8-MOP bath-PUVA.[15, 18] Six other cohort studies[13, 14, 19, 23, 24, 26] and one large population-based case–control study[22] did not find any increased risk of melanoma in psoriasis patients.

We performed a meta-analysis including six studies,[13, 14, 18, 23, 24, 32] the overall SIR was not significantly increased (SIR = 1.07, 95% CI 0.85–1.35; Fig. 8).

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Figure 8. Risk of melanoma in psoriasis: meta-analysis.

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Squamous cell carcinoma

Fourteen studies were selected. We performed a meta-analysis including seven studies,[13, 14, 18, 23, 24, 30, 37] the overall SIR was significantly increased in psoriasis (SIR = 5.31, 95% CI 2.63–10.71; Fig. 9).

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Figure 9. Risk of squamous cell carcinoma in psoriasis: meta-analysis.

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Data from the US PUVA follow-up study clearly associated PUVA therapy with skin cancer, mainly Squamous cell carcinoma (SCC), which also developed on non-exposed skin, including invasive penile SCC.[38] The risk was shown to increase in a linear mode with the cumulative PUVA dose[36] and persisted after treatment cessation.[41] In the last report of the US PUVA follow-up study, accumulating about 30 years of follow-up, the incidence of SCC in psoriasis patients was 32 times higher (95% CI 30.8–33.1) than expected for an age- and gender-matched US general population. Patients exposed to 251–350 PUVA treatments had a four times higher risk of SCC than those exposed to less than 50 PUVA treatments; the risk was the highest for those exposed to more than 450 PUVA treatments. Patients exposed to less than 150 treatments did not experience a clinically important increase in the risk of SCC. Exposure to methotrexate for more than 2 years was a modest additional risk factor for SCC: IRR = 1.74 (95% CI 1.51–2.0).[35]

The level of skin cancer risk appeared to be lower in the European PUVA cohort studies than in the US PUVA cohort.[23, 30, 31]

Marcil et al.[42] reported among the PUVA follow-up study a threefold higher risk of SCC in ciclosporin users than in non-users.

A sixfold higher incidence of skin malignancies as compared with the general population was observed in a cohort of 1252 psoriasis patients treated with ciclosporin, most of which were SCC.[13] All patients with SCC and/or Basal cell carcinoma (BCC) had previously received PUVA. Conversely, Vakeva et al.[33] did not observe any increased risk of skin malignancies in a retrospective cohort study of 272 patients who had received at least 1 month of ciclosporin (mean treatment time = 8 months) and were followed-up for 10.9 years.

High exposure to methotrexate, defined as more than 2–4 years of treatment, appeared to be a significant independent risk factor for developing SCC in the PUVA follow-up study,[37] whereas oral retinoid use appeared to be associated with a reduction in SCC risk.[40] The risk of SCC was modestly increased when PUVA was associated with high UVB exposure.[34] In a recent systematic review, Archier et al.[44] stressed the lack of high quality data to robustly assess the carcinogenic risk of Narrow band UVB.

There was no significant increased risk of SCC in two cohorts of psoriasis patients treated with 8-MOP bath-PUVA.[15, 18]

Basal cell carcinoma

A total of 10 studies were selected.[13-15, 22, 23, 30, 33, 35-37] We performed a meta-analysis including seven studies,[13-15, 23, 30, 33, 37] the overall SIR was significantly increased in psoriasis, but remained lower than the one for SCC: SIR = 2.00 (95% CI 1.83–2.20).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

This SLR shows a tendency towards an increased risk of several solid cancers in psoriasis. It concerns mainly cancers of the upper aerodigestive tract, liver, respiratory tract, pancreas and urinary tract. The only two studies that made adjustments regarding smoking and alcohol consumption[12, 19] did not find any increased risk of total, lung, oesophagus or urinary tract cancers, suggesting a role of tobacco smoking and alcohol consumption in the cancer risk excess observed in psoriasis. The risk of NHL appears to be slightly increased in psoriasis. In two studies,[14, 29] psoriasis appears to be strongly associated with cutaneous lymphomas such as mycosis fungoïdes and CTCL, but this association may rather reflect diagnosis confusion between CTCL and psoriasis than a real association. Some studies tend to show an association between the risk of cancer, particularly lymphoma, and psoriasis severity. As disease severity and treatments are often closely linked, it is difficult to disentangle the role of chronic inflammation vs. the role of systemic agents on cancer risk in severe psoriasis.

Psoriasis patients have an elevated risk of SCC and, to a lesser extent, of BCC. This risk is highly correlated with exposure to PUVA treatment and increases with cumulative PUVA dose. The risk of melanoma does not appear to be increased in psoriasis.

This is to our knowledge, the first SLR including meta-analysis investigating cancer risk in psoriasis. The association between psoriasis and neoplasms is debated: psoriasis has been hypothesized to promote malignancies due to chronic immune system activation and impaired immune surveillance. In addition, immunosuppressive treatments used for psoriasis may also contribute to the overall risk. We have included a large number of epidemiological studies, focusing on analysing cancer risk by organ class. Whenever possible, treatment received for psoriasis and comorbidities contributing to cancer risk – mainly alcohol and smoking – have been taken into account. Meta-analysis has helped to better characterize the level of risk by including studies showing consistency in data reporting quality and analysis methods.

However, it needs to be acknowledged that our work has important limitations. First, the methodological quality of epidemiological studies was highly heterogeneous. In particular, the older studies did not comply with the recently published STROBE criteria which ensure optimal quality of observational studies reported.[45]

There was a large heterogeneity between studies regarding study population, reference population and follow-up. Systemic treatment exposure varied across studies and was sometimes even unspecified. In most studies, information on comorbidities, in particular alcohol and smoking, was not accurately collected and rarely taken into account in the analysis of cancer risk. There was a large heterogeneity in statistical methods used across studies for the risk assessment which could include: RR, IRR, HR, SIR and standard morbidity ratio, thus preventing from combining data. Several studies lacked statistical power due to small sample size or short follow-up. The use of administrative claim databases and/or diagnostic codes (as the International Classification of Diseases for Oncology) in many studies could be a source of coding errors and diagnosis misclassification leading to potential bias.

In conclusion, psoriasis patients tend to have a small increased risk of some solid cancers, especially those linked to alcohol drinking and cigarette smoking. The risk of NHL appears to be slightly higher in psoriasis patients compared with the general population, but it may be overestimated because of misdiagnosis of early CTCL as psoriasis. Psoriasis patients have an increased risk of NMSC, especially SCC, mainly due to previous exposure to PUVA and immunosuppressants including ciclosporin and possibly methotrexate. The risk of melanoma does not appear to be increased significantly. There is a need to obtain data from ongoing psoriasis registries including robust assessment of comorbidities and pharmacological treatments to better characterise the risk of cancer in psoriasis.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References