Histologically verified penile lichen sclerosus—Incidence in Denmark over 26 years and long‐term risk of penile and non‐penile cancer

Abstract

Lichen sclerosus (LSc) is a chronic inflammatory disease affecting the anogenital area and having malignant potential. Population‐based data on the incidence of LSc in men and associated cancer risk are sparse. In the Danish Pathology Register, we identified all men with histologically verified penile LSc 1997–2022 and calculated incidence rates. Through linkage with the Danish Cancer Registry, standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were computed as relative risk estimates of penile squamous cell carcinoma (SCC) and non‐penile cancer in men with penile LSc (1978–2019) compared with background population rates. During the study period, the age‐standardized incidence rate of penile LSc more than doubled, being 17.9 per 100,000 person‐years in the most recent time (2021–2022). The age‐specific incidence increased with age and was highest in ages 70–79 years (29.2 per 100,000 person‐years). Compared with the general population, men with penile LSc had an increased rate of penile SCC (SIR = 15.5, 95% CI: 12.0–19.5), which increased with follow‐up length and younger age at LSc diagnosis. Rates of non‐penile cancers were mostly close to unity except for lung cancer (SIR = 0.6, 95% CI: 0.5–0.7). This nationwide study showed an increased incidence of histologically verified penile LSc over the past 26 years. Importantly, men with penile LSc had nearly 16 times higher rate of penile SCC compared with the general population. There was no strong association with the non‐penile cancers, except for a lower rate of lung cancer, suggesting that the malignant potential of LSc is caused by local factors rather than a general cancer predisposition.

What's new?

About half of penile squamous cell carcinomas are causally associated with inflammatory conditions such as lichen sclerosus (LSc), but few large‐scale studies have assessed the risk of penile cancer in men with LSc. Here, the authors conducted a large nationwide study in Denmark to estimate the risk of penile and non‐penile cancer in men with LSc. They also considered how age at LSc diagnosis contributed to risk. They found that incidence of penile LSc more than doubled between 1997 and 2022, and men with LSc had 16 times higher incidence of penile cancer than the general population.

Abbreviations

CI

confidence interval

HIV

human immunodeficiency virus

HPV

human papillomavirus

ICD

International Classification of Diseases

LSc

lichen sclerosus

SIR

standardized incidence ratio

SNOMED

Systemized Nomenclature of Medicine

1. INTRODUCTION

Lichen sclerosus (LSc) is a chronic inflammatory mucocutaneous disease that has the potential for malignant transformation. ¹ The etiology and pathogenesis of LSc are unclear, although proposed multifactorial causal elements include genetic, immunologic, and infectious factors, as well as physical trauma. ¹ , ² In men, accumulating data support that accentuated exposure of urine to a susceptible epithelium is a causative factor for the development of penile LSc. ² , ³ , ⁴ LSc mostly affects the anogenital area; in men, the glans penis and foreskin. Patients with genital LSc may be asymptomatic or suffer from symptoms such as pruritus, burning, bleeding, tearing, dysuria, or urinary dysfunction. ¹ , ² Clinically, sclerotic scarring can develop into phimosis, meatal stenosis, and proximal urethral strictures. ¹ , ⁵ LSc is often diagnosed clinically, with biopsy verification recommended in cases of differential diagnosis, suspicion of malignancy, or first‐line treatment failure. ¹

The exact incidence of male LSc is unknown as the disease is generally under‐recognized and often misdiagnosed. ¹ A few studies have reported single‐center statistics, ⁶ , ⁷ , ⁸ whereas population‐based incidence rates, to our knowledge, have only been assessed by two studies from Sweden. ⁹ , ¹⁰ The most recent of these demonstrated a relatively stable nationwide incidence of clinically diagnosed LSc from 2001 to 2021. ¹⁰ In contrast, a Finnish single‐center study based on all clinically and/or histologically verified cases of male genital LSc in one hospital district during 2004–2020 reported a more than five‐fold increase in incidence. ⁸

Genital LSc is recognized as a risk factor for the development of penile squamous cell carcinoma (SCC). ¹¹ , ¹² Penile cancers are rare, and the vast majority are SCCs. ¹¹ , ¹³ Approximately half of penile SCCs are caused by human papillomavirus (HPV), ¹⁴ whereas the remaining, the HPV‐independent penile SCCs, are causally associated with chronic inflammatory conditions such as LSc. ¹¹ , ¹² Smaller retrospective case studies have estimated that at least 1%–8% of men with LSc or genital LSc develop penile cancer. ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ On a larger scale, only three studies have assessed the risk of penile cancer in men with LSc, and these studies are also the only ones to report on the risk of non‐penile cancers. ⁸ , ⁹ , ¹⁰ None of these studies considered the temporal order of LSc and cancer and did not investigate whether the risk varied by age at LSc or follow‐up time.

In this large nationwide study, we retrieved information on all incident cases of histologically verified penile LSc in Denmark and assessed the incidence since 1997. In addition, we estimated the risk of subsequent penile SCC and non‐penile cancer in men with penile LSc compared to the general male population and examined patterns in risk in relation to length of follow‐up and age at LSc diagnosis.

2. METHODS

2.1. Study population

We identified all men in Denmark with histologically verified penile LSc from January 1st, 1978, until December 31st, 2022, in the Danish Pathology Register, which holds cytologic and histologic diagnoses conducted at all Danish pathology departments since the 1970s and is considered nearly 100% complete since 1997. ¹⁹ Records are classified according to the Systemized Nomenclature of Medicine (SNOMED). We identified cases of penile LSc by a penile topography code (T76330, T02540, T02530, T76300, T76000, T76320, T76331, and T76310) combined with the LSc morphology code (M58240). For each man, we considered exclusively the first registration of penile LSc.

2.2. Register linkage

In Denmark, linkage between the national registries at the individual level is possible through the unique identification number given to all citizens since 1968. ²⁰ Information on cancers in our cohort was retrieved by linkage to the Danish Cancer Registry, which contains nationwide data on all cancer cases since 1943. ²¹ Reporting has been mandatory since 1987, and the registry is considered to have a high degree of completeness. ²¹ Records are categorized according to the 10th edition of the International Classification of Diseases (ICD‐10) and the third edition of ICD for Oncology (ICD‐O‐3). Information on migration and death was retrieved from the Danish Civil Registration System. ²⁰

2.3. Statistical analysis

Incidence of penile LSc was examined in a 26‐year period (1997–2022). From Statistics Denmark, we obtained aggregated data on male person time at risk for all combinations of age and calendar year, and rates were reported as number of incident cases per 100,000 person‐years. Age‐specific incidence rates were grouped into 5‐year age intervals, and the age‐standardized incidence rates were calculated using the world standard population of Segi and reported in 2‐year periods.

For cancer risk assessment, LSc cases diagnosed during 1978–2019 were included to ensure at least 2 years of follow‐up in the Cancer Registry. All cases of penile LSc with a concurrent or previous cancer diagnosis, except non‐melanoma skin cancer, were excluded prior to analysis, and the cohort was followed from 30 days after the first penile LSc diagnosis until either death, emigration, or January 1st, 2022, whichever came first. We used the Aalen‐Johansen method to calculate the cumulative incidence of penile SCC according to time since penile LSc diagnosis, with the date of penile LSc diagnosis as the starting date, death as a competing event, and censoring at emigration. As relative risk estimates, we calculated standardized incidence ratios (SIRs) with 95% confidence intervals (CIs). SIRs were estimated using log‐linear Poisson models with the number of observed cancer cases in 5‐year age‐ and calendar‐year intervals as the outcome and the logarithm of total follow‐up in person‐years multiplied by the equivalent age‐ and calendar‐year‐specific incidence rates in the general male population in Denmark as offsets. SIRs were calculated for all cancer sites; however, only cancers with five or more observed cases were reported. Additionally, we calculated the SIR according to age at LSc diagnosis (<40 and ≥40 years of age) and length of follow‐up categorized into three (<1 year, 1–4 years and ≥5 years) or four intervals (<1, 1–4, 5–9, and ≥10 years). SIRs by length of follow‐up were reported only for cancer sites with at least 25 observed cases in total. Due to data protection rules at Statistics Denmark, exact numbers of observed cases below five must be masked. All statistical analyses were conducted using R Statistical Software (v4.3.2; R Core Team 2021). ³⁵

3. RESULTS

3.1. Incidence of histologically verified penile LSc

We identified 12,171 men in Denmark registered with histologically verified penile LSc between 1997 and 2022. The median age at penile LSc diagnosis was 50 years. Figure 1 shows the age‐specific incidence rate of penile LSc in 5‐year age intervals. The incidence rate increased with increasing age, being <10 per 100,000 person‐years in men younger than 20 years to an incidence of nearly 30 per 100,000 person‐years in men 70 years and older.

FIGURE 1.

Age‐specific incidence of histologically verified penile lichen sclerosus in Denmark, 1997–2022.

The age‐standardized incidence rate in the period 1997–2022 is shown in Figure 2. Following a relatively stable course during the first 10 years of registration (1997–1998: 7.5 per 100,000 person‐years; 2005–2006: 9.5 per 100,000 person‐years), the incidence increased steeply in 2007–2008 to 2011–2012 (18.8 per 100,000) and hereafter remained at approximately the same high level throughout the study period, being 17.9 per 100,000 person‐years in the most recent calendar period (2021–2022).

FIGURE 2.

Age‐standardized incidence of histologically verified penile lichen sclerosus in Denmark, 1997–2022.

3.2. Cancer risk

A total of 10,592 men with histologically verified penile LSc diagnosed during 1978–2019 and with no previous or concurrent cancer were identified. During the follow‐up time, comprising 118,477 person‐years, we observed 1279 primary cancers.

The crude absolute risk of penile SCC in men with histologically verified penile LSc is illustrated in Figure 3. The cumulative incidence increased steadily over time, with the absolute risk of penile SCC after 10, 20, and 30 years being 0.4% (95% CI: 0.3–0.6), 1.1% (95% CI: 0.8–1.4), and 1.3% (95% CI: 1.0–1.8), respectively. Table 1 presents the SIRs of penile SCC following a histologically verified LSc diagnosis. Compared with the general Danish male population, men with penile LSc had a 15.5‐fold increased risk of penile SCC (95% CI: 12.0–19.5). In an analysis stratified according to age, we found that the SIR for men diagnosed with penile LSc <40 years of age was 26.0 (95% CI: 11.1–47.1) and nearly twice that of men diagnosed with LSc ≥40 years of age (SIR = 14.7, 95% CI: 11.1–18.8), but with overlapping CIs. Regarding length of follow‐up, men with penile LSc had a significantly increased risk of penile SCC across all follow‐up intervals compared to the Danish male population, with a tendency toward increasing SIRs with increasing length of follow‐up, reaching 17.1 (95% CI: 11.3–24.2) ≥10 years after LSc diagnosis.

FIGURE 3.

Cumulative incidence of penile squamous cell carcinoma (SCC) in men with histologically verified penile lichen sclerosus according to time since penile lichen sclerosus (LSc) diagnosis.

TABLE 1.

Standardized incidence ratios for penile squamous cell carcinoma overall and according to age at penile lichen sclerosus diagnosis and length of follow‐up.

	Observed (n)	Expected (n)	SIR (95% CI)
Penile LSc	64	4.1	15.5 (12.0–19.5)
Age at penile LSc diagnosis
<40 years	8	0.3	26.0 (11.1–47.1)
≥40 years	56	3.8	14.7 (11.1–18.8)
Length of follow‐up
<1 year	<5	<5	10.3 (1.9–25.2)
1–4 years	<20	<5	14.9 (8.6–22.8)
5–9 years	17	1.1	15.3 (8.9–23.4)
≥10 years	27	1.6	17.1 (11.3–24.2)

Note: Due to data protection rules at Statistics Denmark, fewer than five observed cases are masked.

Abbreviations: CI, confidence interval; LSc, lichen sclerosus; SIR, standardized incidence ratio.

Table 2 shows SIRs of non‐penile cancers in men with penile LSc. We observed a decreased rate of lung cancer compared to men in the general Danish male population (SIR = 0.6, 95% CI: 0.5–0.7). In contrast, the SIRs were slightly increased for liver cancer (SIR = 1.4, 95% CI: 1.0–2.0) and cancer in the renal pelvis (SIR = 1.5, 95% CI: 0.6–2.8), although not statistically significant for the latter. For the remaining cancer sites, SIRs were close to unity. In analysis according to age at LSc diagnosis, the SIR for lung cancer was 0.2 (95% CI: 0.0–0.6) and 0.6 (95% CI: 0.5–0.8) in men diagnosed with LSc at age <40 and ≥40 years, respectively. The estimates for the remaining cancer sites did not vary substantially with age at LSc diagnosis (data not shown).

TABLE 2.

Standardized incidence ratios for non‐penile cancer among men with penile lichen sclerosus 1978–2019 with follow‐up until 2022.

Cancer site	Observed (n)	Expected (n)	SIR (95% CI)
Oropharyngeal	13	13.3	1.0 (0.5–1.6)
Esophagus	27	24.6	1.1 (0.7–1.6)
Stomach	29	29.2	1.0 (0.7–1.4)
Colorectal	187	172.7	1.1 (0.9–1.2)
Liver	28	19.4	1.4 (1.0–2.0)
Gallbladder and bile ducts	8	6.4	1.2 (0.5–2.3)
Pancreas	32	35.0	0.9 (0.6–1.3)
Larynx	12	14.0	0.9 (0.4–1.4)
Lung	102	166.2	0.6 (0.5–0.7)
Pleura	8	7.3	1.1 (0.5–2.0)
Malignant melanoma	72	63.3	1.1 (0.9–1.4)
Prostate	297	280.1	1.1 (0.9–1.2)
Testicles	12	13.2	0.9 (0.5–1.5)
Kidney	43	36.9	1.2 (0.8–1.5)
Renal pelvis	7	4.8	1.5 (0.6–2.8)
Bladder	115	107.3	1.1 (0.9–1.3)
Meninges and spinal cord	12	9.4	1.3 (0.7–2.1)
Brain	36	28.2	1.3 (0.9–1.7)
Spinal cord and CNS	6	8.0	0.7 (0.3–1.5)
Thyroid	6	5.6	1.1 (0.4–2.1)
Non‐Hodgkin lymphoma	51	63.0	0.8 (0.6–1.0)
Lymphocytic leukemia	20	21.7	0.9 (0.6–1.4)
Myeloid leukemia	9	11.6	0.8 (0.4–1.4)
Myelodysplastic syndrome	15	11.4	1.3 (0.7–2.1)
Bone and connective tissue	8	7.2	1.1 (0.5–2.1)

Note: Only cancer sites of at least five observed cases are reported.

Abbreviations: CI, confidence interval; CNS, central nervous system; SIR, standardized incidence ratio.

Table 3 shows SIRs of non‐penile cancers according to length of follow‐up, categorized into three follow‐up intervals. The SIR for lung cancer persisted to be decreased throughout the follow‐up period and even persisted more than 10 years after penile LSc diagnosis (≥10 years: SIR = 0.6, 95% CI: 0.4–0.8) (data not shown in table). The SIRs for a few other cancers were slightly increased after the longest follow‐up time, for example, colorectal cancer (≥5 years: SIR = 1.2, 95% CI: 1.0–1.4) and brain cancer (≥5 years: SIR = 1.5, 95% CI: 1.0–2.1) (Table 3).

TABLE 3.

Standardized incidence ratios for non‐penile cancer by years of follow‐up, among men with penile lichen sclerosus 1978–2019, with follow‐up until 2022.

Cancer site	Years of follow‐up	Observed (n)	Expected (n)	SIR (95% CI)
Esophagus	<1 year	<5	<5	1.2 (0.1–3.3)
	1–4 years	<10	<10	1.3 (0.6–2.3)
	≥5 years	16	16.1	1.0 (0.6–1.5)
Stomach	<1 year	<5	<5	1.0 (0.1–2.7)
	1–4 years	<15	<10	1.5 (0.8–2.4)
	≥5 years	15	18.9	0.8 (0.4–1.2)
Colorectal	<1 year	6	12.2	0.5 (0.2–1.0)
	1–4 years	50	48.2	1.0 (0.8–1.4)
	≥5 years	131	112.3	1.2 (1.0–1.4)
Liver	<1 year	<5	<5	0.8 (0.0–3.0)
	1–4 years	<15	<10	2.1 (1.0–3.5)
	≥5 years	16	12.8	1.2 (0.7–1.9)
Pancreas	<1 year	<5	<5	0.4 (0.0–1.6)
	1–4 years	<15	<10	1.3 (0.7–2.2)
	≥5 years	18	22.9	0.8 (0.5–1.2)
Lung	<1 year	5	12.3	0.4 (0.1–0.8)
	1–4 years	28	47.3	0.6 (0.4–0.8)
	≥5 years	70	106.6	0.7 (0.5–0.8)
Malignant melanoma	<1 year	<5	<5	0.2 (0.0–0.9)
	1–4 years	<20	<20	1.1 (0.7–1.7)
	≥5 years	52	42.1	1.2 (0.9–1.6)
Prostate	<1 year	21	19.7	1.1 (0.7–1.6)
	1–4 years	83	77.6	1.1 (0.9–1.3)
	≥5 years	193	182.9	1.1 (0.9–1.2)
Kidney	<1 year	<5	<5	1.6 (0.4–3.5)
	1–4 years	<10	<15	0.7 (0.3–1.3)
	≥5 years	32	24.3	1.3 (0.9–1.8)
Bladder	<1 year	9	7.7	1.2 (0.5–2.1)
	1–4 years	31	30.1	1.0 (0.7–1.4)
	≥5 years	75	69.5	1.1 (0.8–1.3)
Brain	<1 year	<5	<5	1.0 (0.1–2.7)
	1–4 years	<10	<10	0.9 (0.3–1.6)
	≥5 years	27	18.0	1.5 (1.0–2.1)
Non‐Hodgkin lymphoma	<1 year	<5	<5	0.7 (0.1–1.7)
	1–4 years	<15	<20	0.7 (0.4–1.2)
	≥5 years	36	41.8	0.9 (0.6–1.2)

Note: Only cancer sites of at least 25 observed cases in total are reported.

Abbreviations: CI, confidence interval; SIR, standardized incidence ratio.

4. DISCUSSION

In this nationwide study based on high‐quality registry‐based data, we found that the incidence of histologically verified penile LSc more than doubled during a 26‐year period. Data showed that histologically verified penile LSc is a disease of middle‐aged and elderly men, with a median age at diagnosis being 50 years and with the highest incidence observed in men 70–79 years of age. Of great importance, follow‐up data showed that men with histologically verified penile LSc had nearly a 16 times higher risk of developing penile SCC compared with the general Danish male population, and with increased risk persisting for more than 10 years. However, the absolute risk of penile SCC was still low (1.3%) after 30 years. Men with penile LSc did not have an increased risk for most non‐penile cancers but a significantly decreased risk of lung cancer compared to the general male population.

Time‐trends in the incidence of LSc in men have previously been examined in two studies. In line with our data, a Finnish study reported a 5.5‐fold increase in the incidence of clinical and/or histologically verified LSc based on a study population of men in a single hospital district during 2004–2020, reaching 27.5 per 100,000 men. ⁸ In contrast, a Swedish nationwide cohort study of exclusively clinically diagnosed LSc found a relatively stable male incidence of LSc in the period 2001–2020 with a mean annual incidence rate of 47.2 cases per 100,000 person‐years. ¹⁰ The higher incidence rate in Sweden compared to Denmark is most likely explained by the definition of cases, as the Swedish study reported on clinical LSc diagnoses, and only a subset of these are biopsied. ¹ Moreover, data from Sweden combined with ours suggest that the increase in Denmark may to some extent reflect an increasing tendency to biopsy lesions suspicious for LSc rather than a true increase in incidence. During the past decades, health care professionals may have developed increasing awareness of the risk of malignant transformation of LSc, affecting the likelihood of histological examination. In women, we have previously observed a similarly marked increase in the incidence of histologically verified vulvar LSc, the female equivalent to penile LSc, ²² in line with pathology data from the Netherlands. ²³ However, data on the epidemiology of LSc are sparse, and firm conclusions on the observed discrepancies in time‐trends cannot be drawn.

Our data show that histologically verified penile LSc is a disease of middle‐aged and elderly men. These findings are consistent with a previous report, ⁶ whereas some other studies have observed a more flat age distribution ¹⁰ or an extra incidence peak in younger adults in addition to late adulthood. ⁷ , ⁸ , ²⁴ We found no incidence peak of penile LSc among young adults in line with our previous study on histologically verified vulvar LSc. ²² An explanation for this could be that biopsies of lesions in young adults are less frequently performed, and studies reporting the bimodal age distribution of both penile ⁷ , ⁸ and vulvar LSc ²⁵ , ²⁶ were primarily based on clinical diagnoses.

We find that men with histologically verified penile LSc have a substantially higher risk of subsequent penile SCC compared to the general male population. Studies assessing the association between LSc and penile cancer are limited, but our results are in accordance with findings from two recent studies. ⁸ , ¹⁰ Both studies used a case–control design and did not provide information on the temporal order of penile LSc and penile cancer.

Importantly, we found that the increased risk of penile SCC persisted across all follow‐up intervals, and even with the highest risk observed 10 years or more after the penile LSc diagnosis and with the risk of penile SCC being higher when LSc was diagnosed at a younger (<40 years) age. In line with this, retrospective studies have reported an average time from LSc diagnosis to penile cancer ranging from three to 30 years. ¹⁵ , ¹⁷ , ¹⁸ However, to our knowledge, we are the first to show that the risk of penile SCC increased with increasing length of follow‐up and with younger age at LSc diagnosis, indicating that the longer the lifespan with an LSc diagnosis, the higher the risk of developing penile SCC. Even so, we find that the absolute risk over time remains relatively low. Genital LSc is considered to be a risk factor for HPV‐independent penile SCC and precursor lesions due to the chronic inflammation of the penile glans and prepuce, ¹¹ , ¹² and the accumulating risk of penile SCC over time could be due to repeated or persistent chronic inflammation potentially promoting malignant transformation.

Our analysis of the non‐penile cancers indicated that LSc is not associated with a general cancer predisposition. In fact, we found that men with histologically verified penile LSc had a decreased risk of lung cancer, which persisted throughout the follow‐up period. We are not aware of any previous studies that have investigated the association between male LSc and lung cancer risk, but a decreased risk of lung cancer in women with vulvar LSc has previously been reported by three studies from Finland, Italy, and our own group in Denmark. ²⁷ , ²⁸ , ²⁹ Given that lung cancer is a smoking‐related disease, a hypothesis could be that patients with LSc smoke less than the general population. However, we found no association between penile LSc and other smoking‐related cancers such as bladder cancer or oropharyngeal cancer, and two previous studies on smoking habits among men with LSc did not support this hypothesis. ¹⁰ , ³⁰ It is therefore plausible that the decreased risk of lung cancer could be due to other factors, such as genetic or immunologic factors, among patients with LSc. When we looked at the risk of non‐penile cancers in relation to time since the penile LSc diagnosis, we found that with increasing follow‐up time, it seemed that both the risk of colorectal cancer and brain cancer were increased in men with LSc when compared to the background population. There are no results from other studies on these cancer sites in relation to male LSc, and these findings should be confirmed in other studies. In contrast, two previous studies found an increased occurrence of prostate and testicular cancer in men with LSc, ⁸ , ¹⁰ whereas we found no association with these cancers.

Strengths of our study include the large study size and the prospective population‐based study design, which allowed us to assess the temporal relationship between penile LSc and subsequent cancer risk. The high degree of completeness of the Danish nationwide registers enabled us to conduct a study with substantial follow‐up time and ensured minimal loss to follow‐up, and due to the high quality of registration in the Cancer Registry, it was possible to restrict observed penile cancers to those of squamous origin. We identified cases of penile LSc by using the Danish Pathology Register, which provided data on cases with a high degree of diagnostic accuracy. However, since genital LSc is typically diagnosed clinically ¹ and biopsy‐verification is mainly performed in cases of suspected neoplastic changes or treatment failure, the observed cancer risk in our data may not be representative of patients with milder disease. In the Pathology Registry, the SNOMED procedure code used for each sample, for example, biopsy or resection, is often registered but circumcision does not have a specific code. Circumcision may be curative for penile LSc when restricted to the foreskin and glans, ¹ , ³¹ and some case studies have further suggested that proper management and treatment, including circumcision, of male genital LSc decreases or abolishes the risk of penile SCC. ⁴ , ³² In addition, our study lacked information on the use of topical corticosteroid treatment, which in vulvar LSc has been shown to reduce the risk of squamous neoplasias. ³³ Thus, we were unable to consider the influence of these two treatment options on the malignant potential of penile LSc. We also had no information on other factors that could potentially affect the risk of penile cancer and other cancers, such as smoking habits, HPV status, and human immunodeficiency virus (HIV) infection. Specifically, HIV is associated with an increased risk of penile cancer ³⁴ ; however, the prevalence of HIV in Denmark is low. Finally, since the reference population, the background male population, likely includes clinically diagnosed cases of LSc, this may reduce the SIR of penile SCC slightly and contribute to an underestimation of the true risk.

In conclusion, we demonstrate that the incidence of histologically verified penile LSc in Denmark more than doubled over the last 26 years and that penile LSc can occur in all ages, although the most common age of diagnosis was 60 years or older. We observe a substantially increased risk of penile SCC in men with penile LSc compared to the general male population, and this risk persisted for 10 years or more after the penile LSc diagnosis. Our findings emphasize the importance of healthcare practitioners being aware of the risk of malignant transformation; however, it should be taken into account that the absolute risk was still low 20–30 years after the LSc diagnosis. We also observed that men with penile LSc had a decreased risk of lung cancer in line with our previous findings for women with vulvar LSc. Underlying mechanisms explaining this association are unknown and warrant further studies.

AUTHOR CONTRIBUTIONS

Marianne Gardar Stærk: Investigation; writing – original draft; methodology. Emma L. Kaderly Rasmussen: Investigation; writing – original draft; methodology. Charlotte Gerd Hannibal: Investigation; methodology; writing – review and editing. Rasmus Hertzum‐Larsen: Software; writing – review and editing; data curation. Louise Baandrup: Conceptualization; investigation; methodology; writing – review and editing. Susanne K. Kjær: Conceptualization; funding acquisition; investigation; methodology; resources; writing – review and editing.

FUNDING INFORMATION

This project was funded by internal funding from the Unit of Virus, Lifestyle and Genes at the Danish Cancer Institute.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

Statistics Denmark's Scientific Board approved the study. According to Danish legislation, no further ethical approval is needed for register‐based studies.

Stærk MG, Kaderly Rasmussen EL, Hannibal CG, Hertzum‐Larsen R, Baandrup L, Kjær SK. Histologically verified penile lichen sclerosus—Incidence in Denmark over 26 years and long‐term risk of penile and non‐penile cancer. Int J Cancer. 2025;157(6):1086‐1093. doi: 10.1002/ijc.35454

DATA AVAILABILITY STATEMENT

All data related to the project are stored at the Danish Cancer Institute's project database at Statistics Denmark (project number 704874), where all the statistical analyses were performed. The data are available after application to and permission from Statistics Denmark. Further information is available from the corresponding author upon request.