Abstract
Background
Radiotherapy is a risk factor for non-melanoma skin cancer (NMSC), specifically basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), but whether features, histology, or recurrence of NMSC after radiotherapy resemble those observed in the general population is unknown.
Methods
A retrospective review (1994–2017) was performed within the Adult Long-Term Follow-Up Program and Dermatology services at Memorial Sloan Kettering. Demographics, clinical features, histology, treatment and recurrence, were collected for this cohort of patients under close medical surveillance. Pathology images were reviewed when available.
Results
Nine hundred forty-six (mean current age 40 years, SD 13) survivors were assessed for NMSC. The mean age of first cancer diagnosis was 16 years (range: 0–40 years; SD 11). The most common diagnosis was Hodgkin lymphoma (34%, n=318). In 63 survivors, 281 primary in-field lesions occurred, of which 273 (97%) were BCC and 8 (3%) SCC. The mean intervals for BCC and SCC from time of radiotherapy to diagnosis were 24 (range, 2–44 years) and 32 years (range, 14–46 years), respectively. The most common clinical presentation of BCC was macule (47%, n=67). The most common histologic subtypes were superficial for BCC (48%, n=131) and in situ for SCC (55%, n=5). Mohs surgery predominated therapeutically (42%, n=117) and mean duration of follow-up after treatment was 6 years (range, 12 days-23 years); 5-year recurrence rate was 1% (n=1).
Conclusions
Most NMSC arising in sites of prior radiotherapy were low-risk subtype. Recurrence was similar to that observed in the general population. Current guidelines recommend surgical intervention for tumors arising in sites of prior radiotherapy, as they are considered to be at high risk for recurrence. These findings suggest an expanded role for less aggressive therapy may be appropriate, but further research is needed.
Keywords: cutaneous keratinocyte carcinoma, survivorship, radiotherapy
INTRODUCTION
Cancer mortality rates are declining worldwide due to improving detection, treatment, and supportive care.1,2 With increased survival, there is an awareness of long-term adverse events resultant to cancer therapy, including diagnosis of subsequent neoplasms. Non-melanoma skin cancer (NMSC), principally basal cell carcinoma (BCC), is the most common subsequent neoplasm arising in childhood cancer survivors, occurring in 1–9% of total survivors and accounting for 41–58% of all subsequent neoplasms.3–7 Although rarely a metastatic tumor,8 NMSC can cause significant disfigurement and local destruction. Radiotherapy is a well-known risk factor for NMSC.9–11 Retrospective studies have associated the use of radiotherapy in tinea capitis12–14 and childhood cancers with subsequent diagnosis of NMSC.3–5,15–19 Furthermore, radiotherapy for childhood cancer is associated with a 6.3-fold increase in risk of NMSC development and 90% of NMSCs occur within the radiation field.4
However, data are lacking on clinical features, histology, outcomes, and recurrence rates of NMSC arising within and outside the radiation field after treatment for childhood cancer. According to the National Comprehensive Cancer Network (NCCN) Guidelines, BCCs and SCCs arising in sites of prior radiotherapy are considered to be at high-risk for recurrence, and this risk factor alone places the patient in the high-risk category, even in the absence of other known high-risk features such as large tumor size or aggressive histologic subtype. Surgery is recommended for primary BCCs and SCCs, but the recommended surgical approaches differ according to risk category.20,21 We aimed to characterize the clinical features, histology, management, and recurrence of NMSC in childhood cancer survivors previously treated with radiation therapy, with the goal of providing more accurate risk classification.
METHODS
A retrospective chart review (1994–2017) was performed of childhood and young adult cancer survivors previously treated with radiotherapy who were referred to the Adult Long-Term Follow-Up Program (LTFU) or the Dermatology Service at Memorial Sloan Kettering Cancer Center (MSKCC). The study was part of an MSKCC protocol approved by our Institutional Review Board. Informed consent was waived due to the retrospective nature of the study. Survivors up to 39 years of age at the time of initial cancer diagnosis were included.22,23
Radiation therapy
Primary cancer diagnosis was defined as the first cancer diagnosis treated with radiation therapy. Maximum radiation dose data was calculated by selecting the highest dosage the patient received if multiple non-overlapping doses were given. For anatomical sites that received multiple courses of overlapping radiation (e.g., cranial and total body irradiation), doses were added to determine the maximum dose of that site. Notably, no patient received radiation therapy following the diagnosis of NMSC.
Non-melanoma skin cancer
Using LTFU, dermatology, and pathology records, the location of each NMSC was determined. A lesion was considered in-field if it occurred within the irradiated skin according to the treatment documentation in the radiation oncology record. The interval from radiation to first NMSC diagnosis was defined as the date of in-field radiation initiation to the date of histopathologically-confirmed NMSC diagnosis.
Clinical features
Two dermatologists evaluated all BCC with available images (140 tumors in 45 survivors) for consensus agreement on clinical features: presence or absence of pigmentation, lesion morphology (macule, papule, plaque, or nodule), and other features known to be associated with BCC.24
Histologic subtypes
Histological subtypes of BCC were classified using NCCN guidelines.20 Low-risk BCC subtypes include superficial, nodular, other non-aggressive growth patterns such as keratotic, infundibulocystic, and fibroepithelioma of Pinkus, or any combination of the aforementioned subtypes. High-risk BCC was considered any tumor with morpheaform, basosquamous, sclerosing, mixed infiltrative, or micronodular features.Tumors that included both a low-risk and high-risk histology were classified as high-risk, as per usual practice.20
Treatment and Outcomes
Treatment modality and recurrence rate were collected from the medical record. Recurrence was defined as histopathological diagnosis of the same tumor type at a previous site of NMSC treatment after a minimum of 3 months of follow-up.25 Duration of follow-up after radiation was defined as the interval from the date of completion of radiation therapy to the date of the last visit to the LTFU or Dermatology Service. Duration of follow-up of treatment was defined as the interval from the date of primary tumor treatment to the date of last follow-up at the LTFU or Dermatology Service.
Statistical analysis
Descriptive methods were used to describe the study participants, radiation therapy received, location of lesions, clinical and dermoscopic features, histology, and treatment. In light of the descriptive nature of this work, no statistical testing was performed.
RESULTS
Cohort characteristics
The cohort included 946 (mean age 40 years, SD 13) childhood and young adult cancer survivors with a history of radiation therapy; 50% were female (n=474) and 87% were white (n=820) (Table 1). The median (range) age at primary cancer diagnosis was 16 (0–40) years and the most common diagnosis was Hodgkin Lymphoma (34%, n=318). The median duration of follow-up after primary cancer diagnosis was 21 years (range, 1 month - 61 years; SD 12 years).
Table 1.
Demographics, cancer diagnosis, and treatment variables among 946 childhood cancer survivors with a history of radiation therapy.
| Demographics | All patients (n=946) | Patients who developed in-field NMSC (n=63) | Patients who did not develop NMSC (n=883) |
|---|---|---|---|
| Gender – n (%) | |||
| Female | 474 (50) | 30 (48) | 439 (50) |
| Male | 472 (50) | 33 (53) | 444 (50) |
| Race – n (%) | |||
| White | 820 (87) | 61 (97) | 759 (86) |
| Black | 60 (6) | – | 60 (7) |
| Asian | 40 (4) | 1 (1) | 39 (4) |
| Other | 26 (3) | 1 (1) | 25 (3) |
| Median age at primary cancer diagnosis (y) (range) | 16 (Birth-40 years) | 16 (1–37 years) | 16 (Birth-40 years) |
| Primary cancer diagnosis – n (%) | |||
| Hodgkin Lymphoma | 318 (34) | 29 (46) | 289 (33) |
| Leukemia | 176 (19) | 17 (27) | 159 (18) |
| Sarcoma | 162 (17) | 6 (9) | 156 (18) |
| CNS Cancer | 134 (14) | 4 (6) | 130 (15) |
| Non-Hodgkin Lymphoma | 64 (7) | 4 (6) | 60 (7) |
| Other | 92 (10) | 3 (5) | 89 (10) |
| Age at first radiation – n (%) | |||
| 0–9 | 239 (25) | 15 (24) | 224 (25) |
| 10–19 | 396 (42) | 25 (40) | 371 (42) |
| 20–29 | 233 (25) | 15 (24) | 218 (25) |
| ≥30 | 78 (8) | 8 (13) | 70 (8) |
| Total radiation events - median | 2 | 2 | 2 |
| Radiation field(s)b – n (%) | |||
| Abdomen | 657 (69) | 5 (8) | 652 (71) |
| Cranial and Spinal | 451 (48) | 29 (46) | 422 (48) |
| Head and Neck | 298 (31) | 20 (32) | 278 (31) |
| Mantle | 216 (23) | 26 (42) | 190 (21) |
| Total Body | 152 (16) | 14 (22) | 138 (16) |
| Pelvis | 96 (10) | 2 (3) | 94 (11) |
| Limbs | 58 (6) | 2 (3) | 56 (6) |
| Total Lymphoid | 8 (1) | – | 8 (1) |
| Inverted Y | 3 (0) | 1 (1) | 2 (0) |
| Maximum radiation dose to any body site (cGy) – n (%) | |||
| 450–2100 | 250 (26) | 21 (33) | 229 (26) |
| 2160–3600 | 266 (28) | 14 (22) | 252 (28) |
| 3625–5200 | 202 (21) | 20 (32) | 182 (21) |
| >5200 | 203 (21) | 7 (11) | 196 (22) |
| Unknown | 25 (3) | 1 (1) | 24 (3) |
| Additional therapy – n (%) | |||
| Chemotherapy | 336 (35) | 56 (89) | 280 (32) |
| Immunotherapy | 1 (0) | – | 1 (0) |
| Endocrine therapy | 4 (0) | 2 (3) | 2 (0) |
| Supportive therapy | 1 (0) | – | 1 (0) |
| Allogeneic transplantation | 150 (16) | 9 (24) | 141 (16) |
| Autologous transplantation | 78 (8) | 7 (11) | 71 (8) |
| Median duration of follow-up after primary cancer diagnosis (y) (range) | 21 (1 month-61 years) | 32 (5–52 years) | 20 (1 month-61 years) |
| Alive – n (%) | 887 (94) | 59 (94) | 828 (94) |
NMSC: Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)
In 63 survivors (8%), 281 primary in-field NMSC (273 BCC and 8 SCC) and 36 out-of-field NMSC (27 BCC and 9 SCC) were diagnosed. The median (range, SD) number of total and in-field NMSC per patient was 1 (1–61, SD 7) and 2 (1–61, SD 8), respectively. The median interval from initiation of radiation therapy to diagnosis of the first primary NMSC was 25 years (range: 3–47; SD 10) (Table 2).
Table 2.
Non-melanoma skin cancer characteristics of 76 adult survivors of childhood and young adult cancer with lesions inside the radiotherapy field (in-field) and outside (out-of-field).
| Type of NMSC | BCC | SCC |
|---|---|---|
| Patients – number (%) | ||
| *Patients with only in-field lesions | 52 (74) | 5 (42) |
| Patients with only out-of-field lesions | 9 (13) | 4 (33) |
| *Patients with in-field and out-of-field lesions | 9 (13) | 3 (25) |
| Total | 70 | 12 |
| Lesions – number (%) | ||
| In-field total | 274 (91) | 8 (47) |
| Primary | 273 | 8 |
| Recurrent | 1 | – |
| Out-of-field | 27 (9) | 9 (53) |
| Primary | 27 | 9 |
| Recurrent | – | – |
| Total: In field + Out-of-field | 301 | 17 |
| Number of primary in-field lesions per patient – number (%) | ||
| 1 | 25 (41) | 4 (67) |
| 2 | 14 (23) | 2 (33) |
| 3 | 6 (10) | – |
| 4 | 3 (5) | – |
| ≥5 | 13 (21) | – |
| Location of primary in-field lesions – number (%) | ||
| Head and neck | 116 (42) | 3 (37) |
| Trunk | 113 (31) | 5 (62) |
| Limb | 43 (16) | – |
| Pelvis | 1 (0) | – |
| Median interval from radiation to development of first in-field lesion, years (range) | 24 (3–44) | 35 (14–47) |
| Median time between first and second primary lesions, years (range) | 0.5 (0–12) | 8 (0–16) |
NMSC: Non-melanoma skin cancer
BCC: Basal cell carcinoma
SCC: Squamous cell carcinoma
The sum of category totals (n=82) is greater than overall number of patients (n=76) as categories are overlapping to reflect 3 patients with both BCC and SCC in-field only lesions, 1 patient with both BCC and SCC in-field and out-of-field lesions, and 2 patients with in-field and out-of-field BCC and out-of-field SCC.
Clinical Features
Of the 281 in-field NMSC, 119 (42%) were on the head/neck, 118 (42%) were on the trunk, and 43 (15%) were on the extremities. Analysis of the 140 in-field BCCs with available images (Table 3) revealed that 69% (n=97) were non-pigmented. The most common clinical morphology was macule (n=67, 47%), followed by papule (n=57, 40%), plaque (n=13, 9%), and nodule (n=6, 4%).
Table 3.
Clinical features of 140 primary basal cell carcinoma inside the radiation field with pathology images available for review, among adult survivors of childhood and young adult cancer.
| Clinical features | n (%) |
|---|---|
| Clinically pigmented | 43 (31%) |
| Macule | 67 (47%) |
| Papule | 57 (40%) |
| Plaque | 13 (9%) |
| Nodule | 6 (4%) |
Only features with a prevalence of ≥3% are included.
Histologic subtypes
Overall, 271 NMSCs were of low-risk histology (87%), 27 were high-risk (8%), and 19 (6%) had no defined histologic subtype (Table 4). Of the 261 in-field BCC with a defined histologic subtype, 237 (91%) were low-risk [131 (51%) superficial, 43 (16%) nodular, 37 (14%) mixed low-risk, and 26 (10%) infundibulocystic] and 24 (9%) were high-risk [7 (29%) infiltrative, 2 (8%) micronodular, and 15 (62%) mixed high-risk]. Of the 7 in-field SCC with a defined histologic subtype, all (100%) were low-risk (in situ).
Table 4.
Histological subtypes of primary basal cell carcinoma and squamous cell carcinoma, inside and outside the radiation field, among 76 adult survivors of childhood and young adult cancer.
| Histological subtypes of primary lesions – number (%) | BCC in-field | SCC in-field | BCC out of field | SCC out of field |
|---|---|---|---|---|
| Low Risk | ||||
| Superficial | 131 (48) | – | 4 (15) | – |
| Nodular | 43 (16) | – | 8 (30) | – |
| Infundibulocystic | 26 (9) | – | 1 (4) | – |
| *Mixed | 37 (13) | – | 7 (26) | – |
| §In situ | – | 7 (87) | – | 5 (55) |
| §Low-risk invasive | – | – | – | 2 (22) |
| Total Low Risk | 237 (87) | 7 (87) | 20 (74) | 7 (77) |
| †Total High Risk | 24 (9) | 0 (0) | 2 (7) | 1 (11) |
| Unknown | 12 (4) | 1 (12) | 5 (18) | 1 (11) |
| Total Lesions | 273 | 8 | 27 | 9 |
BCC: Basal cell carcinoma
SCC: Squamous cell carcinoma
Low risk mixed histology includes any combination of the individual categories
High risk BCC histology includes: morpheaform, basosquamous, sclerosing, mixed infiltrative, micronodular, or tumors that included both a low-risk and high-risk histology (i.e. nodular and infiltrative, etc.); High risk SCC histology includes: acantholytic (adenoid), adenosquamous (showing mucin production), desmoplastic, metaplastic (carcinosarcomatous) or any combination.
Low risk SCC includes any tumors without high-risk features; tumors in this category were further divided into “in situ” and “low-risk invasive”.
Of the 22 out-of-field BCC with a defined histologic subtype, 20 (91%) were low-risk [8 (40%) nodular, 7 (35%) mixed low-risk, 4 (20%) superficial (15%), and 1(5%) infundibulocystic] and 2 were high-risk. Of the 8 out-of-field SCC with available histologic subtype, 7 (87%) were low-risk [5 (62%) in situ lesions and 2 (25%) were low-risk invasive] and 1 (12%) was high-risk.
Primary Treatment
Overall, 265 (94%) of the 281 in-field NMSC underwent further treatment after biopsy; 11 (4%) received no further treatment and 6 (2%) received an unknown treatment modality (Table 5). Mohs micrographic surgery (MMS) was the most common therapy for in-field BCC (42%, n=114), followed by excision (21%, n=58), and electrodessication and curettage (21%, n=58); non-surgical treatments were employed in 33 (12%) cases [5 (2%) CO2 laser ablation, 9 (3%) imiquimod 5% cream, 3 (1%) photodynamic therapy, and 1 other (0.4%)]. For in-field SCC, MMS was the most common therapy (37%, n=3) followed by electrodessication and curettage (25%, n=2).
Table 5.
Treatment of primary basal cell carcinoma and primary squamous cell carcinoma, in the field of prior radiation therapy, among 63 adult survivors of childhood and young adult cancers.
| Treatment for in-field lesions – n (%) | BCC (n=273) | SCC (n=8) |
|---|---|---|
| Mohs | 114 (42) | 3 (37) |
| Electrodessication and curettage | 58 (21) | 2 (25) |
| Excision | 58 (21) | – |
| Shave removal | 10 (4) | – |
| CO2 laser ablation | 5 (2) | – |
| Topical therapy | 28 (10) | – |
| Imiquimod | 9 | – |
| Efudex | 1 | – |
| PDT | 3 | – |
| Cryosurgery and imiquimod | 1 | – |
| None | 10 (4) | 1 (12) |
| Unknown | 4 (1) | 2 (25) |
BCC: Basal cell carcinoma
SCC: Squamous cell carcinoma
Outcomes
The median duration of follow-up after primary treatment for in-field NMSC was 3 years (range, 12 days - 23 years; SD: 5 years). Of the 281 in-field NMSCs, 1 in-field BCC recurred after 3 months. This tumor arose on the scalp and had a high-risk histologic subtype (infiltrative). The primary treatment modality was excision. The recurrent tumor was successfully treated with excision without evidence of recurrence after 8 months of follow-up. No in-field SCCs recurred and no out-of-field BCC or SCC recurred. Among 110 in-field NMSC with at least 5-years of follow-up, the recurrence rate was 1% (n=1).
DISCUSSION
In this retrospective review of 946 adult survivors of childhood and young adult cancer, 76 patients were found to have 318 non-melanomatous skin cancers (NMSC), both inside and outside the field of prior radiotherapy. Notably, in this cohort of patients under close medical surveillance, many lesions were low-risk subtypes, and many survivors had multiple lesions, but the risk of recurrence after treatment was extremely low, and no NMSC appeared among non-white survivors.
The overall prevalence of NMSC calculated in this study (8%) was slightly higher than the overall prevalence of NMSC in the general population (5%)26 and the same as a prior report on patients treated with radiation therapy for tinea capitis.27 Similarly, the range of time between radiation therapy for cancer and diagnosis of NMSC (3–47 years) was akin to prior reports on patients treated with radiation therapy for cancer.28,29 Based on these results, survivors with a history of radiation therapy should start surveillance for NMSC with annual skin exams and dermoscopy, if available, as soon as 2–3 years after treatment and throughout adulthood.
The range of primary in-field BCC per patient revealed a bimodal distribution with 41% (n=25) of patients with 1 primary lesion and 21% (n=13) of patients with ≥5 in-field lesions. The proportion of patients with ≥5 primary lesions in this study is greater than that identified in a report of single and multiple primary tumors in the general population in which 68.9% of patients had 1 lesion, 18.1% had 2, and 12.9% had 3 or more.30
While the majority of in-field BCC were located on the head or neck, more than a third of lesions were found on the chest or back. While the ability to infer anything meaningful from these results is limited as statistical analysis was not performed, this finding may provide rationale for further investigation of tumor location significance. Prior reports have suggested an additive contribution of UV exposure to development of neoplasms in radiation-therapy exposed areas27,31–35 Based on our findings, patients with a history of radiation therapy for childhood or young adult cancer may be just as likely to develop tumors in sites that receive relatively low sun exposure, however further research is needed.
The majority (87%) of the 273 in-field BCC were of a low-risk histologic subtype. Within this group, the greatest number of lesions belonged to the superficial subgroup (48%, n=131), followed by nodular (16%, n=43). These findings are in contrast to prior small case reports which have found the nodular subtype to be the most frequent arising in sites of prior radiotherapy for tinea capitis, comprising between 33% and 60% of total BCC.27,31,32,36 In patients without a history of radiation seen in the outpatient setting,37,38 nodular is also the most common subtype.39 In our work, which includes cancer survivors under close follow-up, the predominance of superficial subtype may represent a characteristic of lesions occurring in fields of radiotherapy for cancer or a form of screening bias. Importantly, dermoscopic features for these radiotherapy-related NMSC are similar features to those encountered in the general population.37 We found a similar frequency of shiny white blotches and strands, which have a high diagnostic accuracy for BCC,40 and support the use of dermoscopy for early detection in this setting.
Current NCCN guidelines suggest that NMSC arising in sites of prior radiotherapy should be treated as high-risk. In such cases, Mohs micrographic surgery (MMS), resection with complete circumferential margin assessment or standard excision with surgical margins wider than those recommended for low-risk cases (4-mm clinical margins recommended for low-risk BCC and 4–6 mm clinical margins recommended for low-risk SCC), postoperative margin assessment and linear or delayed repair is indicated for surgical candidates and radiotherapy for non-surgical candidates.20,21 Notably, the overall rate of recurrence for BCC in our population (0.4%) of tumors was similar to those observed in the general population also treated with MMS (2.4% - 3.4%),41,42 and the 5-year recurrence rate in our cohort was 1% (n=1), similar to the general population.41,43,44 In addition, low risk clinical and histologic subtypes of NMSC were predominant in our cohort. Therefore, neither the observed recurrence nor histologic subtype support characterizing these radiotherapy-related tumors as high-risk, although investigating less intensive therapy in a research setting would be prudent.20,21
Furthermore, MMS is labor intensive and costly.45,46 In larger lesions, surgery can further contribute to local disfigurement and aesthetic outcomes may be suboptimal.45 Additionally, although most excisions are performed using local anesthetic, more complex cases require general anesthesia,47 exposing survivors to unnecessary risk.48,49 Non-surgical therapies, including 5-fluorouracil, topical imiquimod, photodynamic therapy or cryosurgery achieve optimal cosmetic outcomes with relatively low risk to patients.50–52 Our findings suggest that for childhood and young adult cancer survivors with in-field NMSC with low risk histological and clinical features, dermatologic therapy options with lower costs and risks should be considered in the shared decision-making process.
Limitations of this study include a study population from a single institution, although the number of childhood and young adult cancer survivors included in this work is quite large. It is likely that the duration and intensity of surveillance received by our survivors is greater than survivors in the general population, although the prevalence of NMSC in this population was similar to prior reports. Furthermore, our patients are often treated with MMS. As such, recurrence rate comparisons between this cohort and the general population were only possible using tumors treated exclusively with MMS. Further limitations include the absence of a control group; however, comparison to patients with NMSC in the general population yielded promising results. Dermoscopic review of NMSC showed similar features to other reports on patients in the general population, indicating dermoscopy can be used for efficient early detection in previously irradiated survivors. Additionally, clinical and histopathological features of NMSC in this population were lower-risk than in the general population and few recurrences after MMS were observed, all suggesting that this study population is applicable to other populations of childhood cancer survivors with a history of radiotherapy.
Conclusion
Among childhood cancer survivors, most NMSC arising in sites of prior radiotherapy are of low-risk histologic subtypes and recurrence is rare. Childhood and young adult cancer survivors with in-field NMSC should consider less intense dermatologic therapies during the shared decision-making process.
Acknowledgements
The authors would like to acknowledge Roberto Adsuar, MS, for assistance with initial data collection.
Funding: This work is supported by the National Institutes of Health (P30CA008748, R25CA020449); and the Meg Berté Owen Fund
Conflict of Interest Disclosures:
Dr. Lacouture serves as a consultant for Quintiles, AstraZeneca, Legacy Healthcare, Foamix, Adgero Bio Pharmaceuticals, Janssen R&D and Novocure. Dr. Lacouture also receives research support from Bristol-Myers Squibb. These conflicts do not apply to the current study.
Abbreviations
- BCC
basal cell carcinoma
- LTFU
Long-term follow-up
- KC
keratinocyte carcinoma
- SCC
squamous cell carcinoma
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