To the Editor,
1.
We read with interest the recent report by Barbui and Ghirardi [1] describing subtype‐specific risks of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in patients with myeloproliferative neoplasms (MPN). In their nested case‐control analysis, the authors identified distinct clinical associations between non‐melanoma skin cancer (NMSC) subtypes, particularly the preferential association of SCC with cytoreductive therapies and the less favorable outcomes observed in SCC compared with BCC.
Despite both being classified as NMSC, BCC [2] and SCC [3] differ substantially in biological behavior and clinical implications [4, 5]. However, data addressing subtype‐specific temporal patterns of skin cancer occurrence across the MPN disease course remain limited, particularly with respect to malignancies arising before and after MPN diagnosis and the longitudinal evolution of distinct NMSC subtypes [6, 7].
To investigate subtype‐specific NMSC patterns, we analyzed a longitudinal cohort of 1968 patients with polycythemia vera (PV) and essential thrombocythemia (ET) followed at Mayo Clinic between 1970 and 2024. Institutional review board approval was obtained from Mayo Clinic in accordance with the Declaration of Helsinki; informed consent was waived due to the retrospective nature of the study. The underlying PV/ET cohort has been previously reported in an analysis of autoimmune/inflammatory diseases (AID) and second malignancies [8]; the present study addresses a distinct question focused on subtype‐specific longitudinal patterns of BCC and SCC before and after MPN diagnosis. Patients were classified according to the first post‐MPN NMSC subtype, including first post‐MPN BCC and SCC. Patients developing both subtypes during follow‐up were assigned according to the subtype occurring first after MPN diagnosis. Prior malignancies, including BCC, SCC, and non‐cutaneous cancers occurring before or at MPN diagnosis, were specifically recorded. Hydroxyurea exposure was evaluated in sensitivity analyses restricted to patients receiving hydroxyurea monotherapy or no cytoreductive therapy, excluding those treated with other cytoreductive agents or sequential/combination cytoreductive regimens. Cumulative incidence functions for post‐MPN BCC and SCC were estimated accounting for death as a competing event. Factors associated with subtype‐specific NMSC occurrence were evaluated using Fine‐Gray competing‐risk regression models, with MPN subtype included in multivariable analyses, and expressed as subdistribution hazard ratios (sHRs). Comparisons between groups were performed using Kruskal‐Wallis tests for continuous variables and chi‐square or Fisher's exact tests for categorical variables. Statistical significance was defined as a two‐sided p‐value < 0.05. All statistical analyses were performed using R version 4.4.3.
Among 1968 patients with PV and ET, 190 (9.7%) developed post‐MPN non‐melanoma skin cancers (NMSC), including 65 first post‐MPN basal cell carcinomas (BCC) and 125 first post‐MPN squamous cell carcinomas (SCC). Baseline characteristics according to first post‐MPN NMSC subtype are summarized in Table 1, with detailed pairwise comparisons reported in Table S1. While the distribution of BCC and SCC before MPN diagnosis was relatively balanced (53% and 47%, respectively), the post‐MPN setting showed a marked predominance of SCC over BCC (66% and 34%, respectively). Compared with patients without post‐MPN NMSC, patients developing SCC were older (median age 68 vs 59 years, p < 0.001) and more frequently male (58% vs 43%, p = 0.001). SCC patients were also more commonly affected by PV compared with patients without NMSC (61% vs 50%, p = 0.024), with a borderline enrichment compared with BCC patients (61% vs 46%, p = 0.054). Compared with patients developing BCC, SCC patients showed lower platelet counts (533 vs 685 × 109/L, p = 0.002) and higher hemoglobin levels (16.4 vs 15.4 g/dL, p = 0.036). Absolute neutrophil counts were higher in SCC patients than in patients without NMSC (7.6 vs 6.4 × 109/L, p = 0.006). Hypertension (68% vs 51%, p < 0.001) and hyperlipidemia (61% vs 46%, p = 0.001) were more frequent among SCC patients than among patients without NMSC. Arterial thrombosis after MPN diagnosis occurred more commonly in SCC (23%) and BCC (20%) patients than in patients without NMSC (11%; p < 0.001 and p = 0.017, respectively), while fibrotic progression was enriched in SCC patients (25% vs 16%, p = 0.008). Prior malignancies before or at MPN diagnosis were more frequent among patients subsequently developing BCC (43%) or SCC (29%) than among patients without NMSC (13%, both p < 0.001). Prior BCC was strongly enriched among patients subsequently developing post‐MPN BCC (20% vs 3% in SCC, p < 0.001), whereas prior SCC was more common among both BCC (14%) and SCC (9%) patients than among those without NMSC (1%, both p < 0.001). Longitudinal subtype evolution differed substantially between groups: 25% of patients with first post‐MPN BCC subsequently developed SCC, whereas only 8% of SCC patients subsequently developed BCC. Hydroxyurea exposure was more frequent among SCC patients than those without NMSC (96% vs 84%, p = 0.003), whereas differences between BCC patients and patients without NMSC were less pronounced (92% vs 84%, p = 0.131). Exploratory molecular analyses further demonstrated enrichment of TET2 mutations among SCC patients compared with those without NMSC (34% vs 12%, p < 0.001) and BCC (34% vs 8%, p = 0.019).
TABLE 1.
Clinical, laboratory, and molecular characteristics at diagnosis and during follow‐up of patients with PV and ET stratified by first post‐MPN NMSC subtype: no post‐MPN NMSC, post‐MPN BCC, and post‐MPN SCC. p values refer to overall comparisons across the three groups, with statistically significant values shown in bold.
| Variables | No post‐MPN NMSC (n = 1778) | Post‐MPN BCC (n = 65) | Post‐MPN SCC (n = 125) | p |
|---|---|---|---|---|
| Age in years; median (range) | 59 (18–96) | 65 (30–92) | 68 (35–93) | < 0.001 |
| Age ≥ 60 years old; n (%) | 850 (48) | 38 (58) | 89 (71) | < 0.001 |
| PV cases; n (%) | 895 (50) | 30 (46) | 76 (61) | 0.058 |
| Females; n (%) | 1021 (57) | 32 (49) | 53 (42) | 0.002 |
| Hemoglobin, g/dL; median (range) | 16 (10–24.3) | 15.4 (11.1–20) | 16.4 (11.1–24) | 0.032 |
| Platelets, × 109/L; median (range) | 617 (100–3460) | 685 (194–2300) | 533 (122–2043) | 0.002 |
| Leukocytes, × 109/L; median (range) | 9.4 (1.7–43.4) | 9.2 (4.7–21.4) | 10.2 (4.6–48.1) | 0.359 |
|
Absolute neutrophil count, × 109/L; median (range) N evaluable = 1382 |
6.4 (0.5–29.6) | 6.1 (2.5–18.4) | 7.6 (2.4–23.6) | 0.019 |
|
Absolute monocyte count, × 109/L; median (range) N evaluable = 1372 |
0.6 (0–4.1) | 0.6 (0.1–1.8) | 0.6 (0–3.1) | 0.433 |
|
Absolute lymphocyte count, × 109/L; median (range) N evaluable = 1324 |
1.7 (0.2–6.2) | 1.8 (0.6–4) | 1.6 (0.4–6.9) | 0.164 |
|
Cardiovascular risk factors; n (%) N evaluable = 1934 |
||||
| Diabetes Mellitus; n (%) | 213 (12) | 5 (8) | 21 (17) | 0.167 |
| Hypertension; n (%) | 891 (51) | 37 (59) | 84 (68) | < 0.001 |
| Smoking; n (%) | 274 (16) | 7 (11) | 20 (16) | 0.604 |
| Hyperlipidemia; n (%) | 821 (46) | 37 (57) | 76 (61) | 0.002 |
| Venous thrombosis at/prior to diagnosis; n (%) | 222 (12) | 10 (15) | 12 (10) | 0.485 |
| Arterial thrombosis at/prior to diagnosis; n (%) | 239 (13) | 6 (9) | 25 (20) | 0.068 |
| Venous thrombosis after diagnosis; n (%) | 178 (10) | 7 (11) | 16 (13) | 0.603 |
| Arterial thrombosis after diagnosis; n (%) | 188 (11) | 13 (20) | 29 (23) | < 0.001 |
| Fibrotic progression; n (%) | 280 (16) | 15 (23) | 31 (25) | 0.011 |
| Leukemic transformation; n (%) | 71 (4) | 1 (1) | 5 (4) | 0.604 |
| Follow‐up in years; median (range) | 8.3 (0.1–53) | 10 (1.1–30) | 12.6 (0.8–33.1) | < 0.001 |
| Deaths; n (%) | 532 (30) | 21 (32) | 48 (38) | 0.131 |
| All cancers before/at MPN; n (%) | 227 (13) | 28 (43) | 36 (29) | < 0.001 |
| Cancers before/at MPN excluding NMSC; n (%) | 178 (10) | 10 (15) | 22 (18) | 0.013 |
| Cancers before/at MPN excluding NMSC and hematologic malignancies; n (%) | 155 (9) | 10 (15) | 20 (16) | 0.006 |
| Cancers after MPN excluding NMSC; n (%) | 215 (12) | 6 (9) | 13 (10) | 0.679 |
| Cancers after MPN excluding NMSC and hematologic malignancies; n (%) | 177 (10) | 6 (9) | 12 (10) | 0.975 |
| SCC before MPN; n (%) | 21 (1) | 9 (14) | 11 (9) | < 0.001 |
| BCC before MPN; n (%) | 29 (2) | 13 (20) | 4 (3) | < 0.001 |
| SCC after MPN; n (%) | — | 16 (25) | — | — |
| BCC after MPN; n (%) | — | — | 10 (8) | — |
| AID before/at MPN; n (%) | 108 (6) | 5 (8) | 8 (6) | 0.861 |
| AID after MPN; n (%) | 38 (2) | 2 (3) | 3 (2) | 0.866 |
| AID before/at or after MPN; n (%) | 142 (8) | 6 (9) | 9 (7) | 0.886 |
|
Hydroxyurea exposure; n (%) N evaluable = 1211 |
898 (84) | 46 (92) | 89 (96) | 0.004 |
|
Abnormal Karyotype; n (%) N evaluable = 1418 |
119 (9) | 8 (16) | 12 (15) | 0.079 |
|
Driver mutations; n (%) N evaluable = 1955 | ||||
| JAK2 | 1438 (82) | 53 (81) | 109 (88) | 0.148 |
| MPL | 28 (2) | 0 (0) | 1 (1) | |
| CALR type 1/1‐like | 134 (8) | 4 (6) | 10 (8) | |
| CALR type 2/2‐like | 94 (5) | 3 (5) | 0 (0) | |
| Triple negative | 72 (4) | 5 (8) | 4 (3) | |
|
Next‐generation sequencing; n (%) N evaluable = 620 | ||||
| TET2; n (%) | 65 (12) | 2 (8) | 14 (34) | < 0.001 |
| ASXL1; n (%) | 41 (7) | 3 (12) | 2 (5) | 0.529 |
| TP53; n (%) | 12 (2) | 0 (0) | 1 (2) | 0.760 |
| SRSF2; n (%) | 14 (2) | 1 (4) | 2 (5) | 0.615 |
| SF3B1; n (%) | 12 (2) | 2 (8) | 1 (2) | 0.158 |
| DNMT3A; n (%) | 29 (5) | 3 (12) | 1 (2) | 0.209 |
| EZH2; n (%) | 11 (2) | 0 (0) | 0 (0) | 0.518 |
| SH2B3; n (%) | 8 (1) | 0 (0) | 0 (0) | 0.620 |
| KIT; n (%) | 6 (1) | 1 (4) | 1 (2) | 0.337 |
Abbreviations: AID, autoimmune/inflammatory diseases; BCC, basal cell carcinoma; ET, essential thrombocythemia; MPN, myeloproliferative neoplasm; NMSC, non‐melanoma skin cancer; PV, polycythemia vera; SCC, squamous cell carcinoma.
Cumulative incidence analyses demonstrated distinct subtype‐specific patterns for SCC and BCC development after MPN diagnosis (Figure 1). Patients with prior SCC showed a markedly increased cumulative incidence of subsequent SCC compared with patients without prior SCC (Gray's test p < 0.001). Similarly, prior BCC was strongly associated with subsequent BCC occurrence (Gray's test p < 0.001). In univariable Fine‐Gray competing‐risk analyses (Table S2), SCC risk was associated with male sex (sHR 2.00; p < 0.001), older age at MPN diagnosis (sHR 1.50 per 10 years; p < 0.001), hydroxyurea exposure (sHR 4.37; p = 0.004), prior non‐NMSC cancer history (sHR 2.48; p < 0.001), prior BCC (sHR 4.10; p < 0.001), and prior SCC (sHR 11.84; p < 0.001). Hyperlipidemia, lower platelet count, higher hemoglobin levels, and TET2 mutations were also associated with increased SCC risk. For BCC, significant associations were observed for older age (sHR 1.35 per 10 years; p < 0.001), prior non‐NMSC cancer history (sHR 1.97; p = 0.032), prior BCC (sHR 13.86; p < 0.001), and prior SCC (sHR 10.68; p < 0.001), whereas hydroxyurea exposure was not significantly associated with BCC risk. AID history was not associated with either SCC or BCC risk.
FIGURE 1.
Cumulative incidence of post‐MPN non‐melanoma skin cancer according to prior subtype history. Cumulative incidence functions for post‐MPN squamous cell carcinoma (SCC) (A) and post‐MPN basal cell carcinoma (BCC) (B) according to prior history of the same subtype before or at MPN diagnosis. Death was treated as a competing event. Numbers at risk and cumulative events are reported below each panel.
Multivariable models including MPN subtype are shown in Figure 2. For SCC, older age at MPN diagnosis (sHR 1.31 per 10 years; p < 0.001), male sex (sHR 1.65; p = 0.005), prior BCC (sHR 2.35; p = 0.009), prior SCC (sHR 6.28; p < 0.001), and prior non‐NMSC cancer history (sHR 2.04; p = 0.002) were independently associated, whereas PV was not. Hydroxyurea remained borderline in sensitivity analysis including MPN subtype (sHR 2.76; p = 0.053; Table S3). For BCC, older age (sHR 1.18 per 10 years; p = 0.033), prior BCC (sHR 8.55; p < 0.001), prior SCC (sHR 4.75; p < 0.001), and prior non‐NMSC cancer history (sHR 2.20; p = 0.019) were independent predictors. Hydroxyurea was not associated with BCC risk (Table S4). TET2 mutations were associated with SCC risk in univariable analysis (sHR 2.67; p = 0.002), retaining directionality after multivariable adjustment including MPN subtype (sHR 1.85; p = 0.086; Table S5).
FIGURE 2.
Multivariable Fine‐Gray competing‐risk analyses for subtype‐specific post‐MPN non‐melanoma skin cancer risk including MPN subtype. Forest plot showing multivariable Fine‐Gray competing‐risk regression models for post‐MPN squamous cell carcinoma (SCC; upper panel) and basal cell carcinoma (BCC; lower panel), including MPN subtype coded as PV versus ET. Results are reported as subdistribution hazard ratios (sHRs) with 95% confidence intervals. Red markers indicate statistically significant associations. *Prior cancer excludes prior BCC and SCC.
In secondary survival analyses restricted to patients developing post‐MPN NMSC, patients with SCC showed a non‐significant trend toward inferior survival compared with those developing BCC (log‐rank p = 0.15; Figure S1). However, patients with SCC were older at first post‐MPN NMSC diagnosis compared with those developing BCC (median 76.6 vs 71.7 years, p = 0.013), and SCC subtype was not independently associated with survival after adjustment for age at first NMSC and sex (HR 1.04, 95% CI 0.62–1.76; p = 0.88).
Our study provides a dedicated competing‐risk analysis of SCC and BCC development in MPN and suggests that these entities should not be considered biologically interchangeable secondary malignancies. While prior studies reported increased NMSC burden in MPN, most evaluated composite cutaneous endpoints or were primarily treatment‐centered. Our longitudinal approach extends the MPN‐K observations by showing distinct pre‐ and post‐MPN BCC/SCC trajectories, suggesting host susceptibility beyond treatment exposure alone. By contrast, our findings support distinct subtype‐specific risk profiles. The strongest associations involved prior cutaneous cancer history: prior SCC independently predicted subsequent SCC, whereas prior BCC strongly predicted future BCC, supporting persistent phenotype‐specific susceptibility and field cancerization. Cross‐phenotype associations also remained evident after multivariable adjustment, suggesting partially shared host predisposition mechanisms. SCC appeared more strongly associated with systemic and host‐related factors, including older age, male sex, and prior non‐NMSC cancer history, whereas BCC risk was driven mainly by prior oncologic and cutaneous cancer history; PV versus ET was not independently associated with either endpoint. Clinically, they support subtype‐specific dermatologic surveillance, particularly among MPN patients with prior cutaneous cancer. This concept is consistent with recent observations in ruxolitinib‐treated patients, in whom NMSC showed aggressive behavior, with SCC predominance, high recurrence, and metastatic NMSC as a major cause of death [9]. Future studies should distinguish BCC from SCC when evaluating treatment‐associated risk, host susceptibility, and cancer‐related outcomes. Hydroxyurea exposure was associated with SCC in univariable analyses and remained borderline after multivariable adjustment, with no signal for BCC, suggesting possible confounding by susceptibility, disease duration, or inflammatory burden. Exploratory analyses identified a potential association between TET2 mutations and SCC risk, biologically intriguing given the role of TET2‐dependent epigenetic regulation in SCC tumorigenesis [10].
The main limitations include retrospective design, lack of detailed UV exposure/actinic damage data, variable dermatologic surveillance and NMSC ascertainment, and limited molecular characterization. Strengths include long‐term follow‐up, subtype‐specific analyses, and Fine‐Gray competing‐risk methodology accounting for mortality. Overall, our findings support SCC and BCC in MPN as partially distinct clinical‐biologic phenotypes with different associations and potentially different pathogenic mechanisms.
Author Contributions
G.G.L., N.G., and A.T. conceived and designed the study. G.G.L., N.G. collected the data. G.G.L. performed statistical analyses. G.G.L. drafted the manuscript. N.G., P.G., A.P., A.M.V., A.T. reviewed and edited the manuscript.
Funding
The authors have nothing to report.
Conflicts of Interest
G.G.L. received honoraria from Novartis, GSK, AOP; N.G. has served on the Advisory Board for DISC Medicine and Agios; P.G. received honoraria from Novartis, GSK, AOP; A.M.V. received honoraria from Incyte, Novartis, GSK, AOP, Italfarmaco. All other authors declare no conflicts of interest.
Supporting information
Table S1: Clinical, laboratory, and molecular characteristics according to first post‐MPN NMSC subtype.
Table S2: Univariate Fine‐Gray competing‐risk analyses for post‐MPN SCC and BCC.
Table S3: Multivariable Fine‐Gray competing‐risk analysis for post‐MPN SCC risk including hydroxyurea exposure and MPN subtype.
Table S4: Multivariable Fine‐Gray competing‐risk analysis for post‐MPN BCC risk including hydroxyurea exposure and MPN subtype.
Table S5: Exploratory multivariable Fine‐Gray competing‐risk analysis for post‐MPN SCC risk in molecularly annotated patients, including MPN subtype.
Figure S1: Overall survival after first post‐MPN non‐melanoma skin cancer according to subtype.
Contributor Information
Giuseppe G. Loscocco, Email: giuseppegaetano.loscocco@unifi.it.
Ayalew Tefferi, Email: tefferi.ayalew@mayo.edu.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Clinical, laboratory, and molecular characteristics according to first post‐MPN NMSC subtype.
Table S2: Univariate Fine‐Gray competing‐risk analyses for post‐MPN SCC and BCC.
Table S3: Multivariable Fine‐Gray competing‐risk analysis for post‐MPN SCC risk including hydroxyurea exposure and MPN subtype.
Table S4: Multivariable Fine‐Gray competing‐risk analysis for post‐MPN BCC risk including hydroxyurea exposure and MPN subtype.
Table S5: Exploratory multivariable Fine‐Gray competing‐risk analysis for post‐MPN SCC risk in molecularly annotated patients, including MPN subtype.
Figure S1: Overall survival after first post‐MPN non‐melanoma skin cancer according to subtype.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.