Cutaneous radiation syndrome

Radiation damage to the skin of radiation protection workers already occurred in the early days of experiments with radioactivity. Röntgen announced his discovery of X-rays in January 1896, the same year that Becquerel announced the discovery of the radioactivity of uranium. Grubbé recognized the destructive power of X-rays and treated a woman with breast cancer in January 1896, just 23 days after Röntgen's report. Even the Nobel Prize winner Marie Curie suffered radiation-induced skin damage on her hands because she handled radium samples during her experiments. Some types of skin damage, such as carcinomas of the skin, did not show up until 10-30 years later after the early radiologists exposed their hands during fluoroscopic examinations.

The term"cutaneous radiation syndrome (CRS)" is used to describe radiation damage to the skin and deeper soft tissues. This can be caused by the absorption of energy after acute or chronic exposure to ionizing radiation and leads to early or delayed tissue damage. The damage is usually limited to a specific area of the body (International Atomic Energy Agency 2020). Their intensity, duration and severity are dose-dependent (Gottlöber P et al. 2001). The damage mainly depends on the volume of the irradiated tissue, the absorbed dose, the radiation quality and the inherent factors of the exposed persons (comorbidities or genetic disposition).

Since 1993, the term "cutaneous radiation syndrome" has been used for cutaneous manifestations after exposure to ionizing radiation with the stages:

• prodromal erythema
• Manifestation stage
• Subacute stage
• Chronic stage. In this stage, unlike burns, the fibrosis of cutaneous radiation syndrome is chronically progressive.

Radiation recall: Some chemotherapeutic agents lead to additional sensitization of the skin or other tissues to ionizing radiation. Radiation recall is a rare but characteristic side effect of oncological chemotherapy or immunotherapy.

The effects of radiotherapy (RT) on the skin can also vary due to the different radiosensitivity of the various cells. For example, hair follicle stem cells, melanocytes and cells in the basal keratinocyte layer tend to react more strongly to radiation exposure and thus contribute to more far-reaching cutaneous consequences (Rachidi W et al. 2007).

The immune system reacts to radiation-damaged cells in a particular way: apoptotic, non-viable cells release inflammatory mediators (damage-associated molecular patterns = DAMPs) (Carvalho HA et al. 2018; Schaue D 2017). It is known that neutrophils are the first inflammatory cells to be recruited lesionally. Their presence leads to the release of various cytokines: tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1) and 6 (IL-6), among others. These cytokines are able to increase inflammation. They are held responsible for the development of fibrosis. Attracted monocytes differentiate into M1 and M2 macrophages in the lesion. M2 macrophages secrete transforming growth factor beta (TGF-β), one of the central players in radiation fibrosis. TGF-beta1 production is increased immediately after exposure to ionizing radiation, the amount of TGF-beta1 released appears to correlate with the radiation dose and can remain high for many months.

There are 3 different isoforms of TGF-beta, TGF-β1, TGF-β2,TGF-β3, with TGF-beta1 occurring most frequently in fibroproliferative diseases. TGF-beta is a protein that can regulate fibrogenesis by inducing the proliferation of postmitotic fibrocytes from progenitor fibroblasts. These fibrocytes have the ability to produce collagen. TGF-beta can also induce excessive deposition of extracellular matrix by

• upregulating the tissue inhibitors of metalloproteinases (TIMPs)
• and
• dysregulating the activity of matrix metalloproteinases (MMPs) (MMP-2 and MMP-9).

Finally, TGF-beta induces the formation of collagen, fibronectin and proteoglycans by leading to the differentiation of fibroblasts into myofibroblasts. It is known that this secretion leads to an increase in tissue strength and thickness.

Many studies have shown that the concentrations of TGF-beta, mainly TGF-β1, increase after irradiation in human and animal models, while they remain unchanged in non-irradiated tissue (Pohlers D et al. 2009). TGF-β levels also increase with additional doses of RT (de Andrade CBV et al. 2017). In addition, patients with higher plasma TGF-β1 levels have a higher risk of developing radiation-induced fibrosis. The elevated TGF-β levels can be detectable even months and years after the end of therapy. Interestingly, tissue fibrosis was also observed when TGF-β was administered to healthy, non-irradiated animals. In contrast, when patients were treated with liposomal Cu/Zn superoxide dismutase, an agent that downregulates TGF-β, the radiation-induced fibrosis was reversed (Lewanski CR et al. 2001).

TGF-beta1 production is increased immediately after exposure to ionizing radiation, the amount of TGF-beta1 released appears to correlate with the radiation dose and can remain elevated for many months. The persistent chronic inflammation leads to an overexpression of interleukin-4, interleukin-13 (T-helper-2 cytokines) and the growth factor PDGF, which enables a long-lasting presence of myofibroblasts in the injured tissue. The result is poor wound healing with reduced local vascularization and excessive (non-productive) fibrosis with excessive deposition of collagen, fibronectin and hyaluronic acid in the pre-irradiated subdermal tissue. The resulting fibrotic and vascularized tissue is functionally inferior and generally susceptible to wound healing disorders.

The effects of radiotherapy (RT) on the skin can also vary due to the different radiosensitivity of the various cells. For example, hair follicle stem cells, melanocytes and cells in the basal keratinocyte layer tend to respond more strongly to radiation exposure and thus contribute to more extensive cutaneous consequences (Rachidi W et al. 2007).

Fibrosis is one of the many RT side effects associated with molecular and cellular events that define radiosensitivity. It is characterized by the induction of DNA damage and tissue inflammation. In fact, irradiation triggers many different types of DNA damage. DNA double-strand breaks (DSBs) are the most severe and difficult to repair. The repair kinetics of DNA DSBs is an important factor in determining radiosensitivity. Many studies have shown a correlation between unrepaired DSBs and radiation-induced toxicities (Terasaki Y et al. 2011).

In addition to direct damage to cellular DNA, ionizing radiation leads to the formation of reactive nitrogen and oxygen molecules (ROS), which interact with water molecules in the cell nucleus and lead to the formation of hydroxyl radicals. These radiation-induced radicals are responsible for more than 2/3 of the DNA DSB in the case of X-rays, but can also damage other cellular components such as proteins, membranes and RNA.

When assessing the severity of CRI, the energy of the radiation to which the skin has been exposed is the most important parameter. The clinical signs of radiation injury vary depending on the dose and duration of exposure, but generally manifest themselves in several well-defined responses that may be spread over time. These include:

• Erythema (redness, similar to sunburn)
• Alopecia (hair loss due to follicle damage)
• Dry desquamation of the skin
• Moist desquamation of the skin (characterized by oozing/fluid loss)
• Local edema (swelling of the region where the CRI is located)
• Hyperpigmentation
• Atrophy of the skin
• Vascular damage with rarefaction of vessels
• Local telangiectasia
• Local fibrosis
• Ulceration
• Necrosis

In some cases, high radiation doses can also damage other, non-epithelial tissue, such as the underlying fat and muscle tissue. This complication can lead to an even worse prognosis for the patient in terms of healing and long-term prospects.

Unlike burns, LRI (local radiation injury) and CRI (cutaneous radiation injury) develop over a longer period of time and involve periods of latency interrupted by active inflammation. Cutaneous radiation injuries heal slowly (not comparable to thermal injuries), the strength of the closed wound is lower and the pain associated with the injury is usually much more severe (Jose de Lima Valverde N et al. 2010). For equivalent doses of radiation, topography is a determining factor in the severity and speed of onset of manifest radiation symptoms, with the face, chest and neck (areas with relatively thin skin) responding earlier and with more severe injuries than areas of the body with thicker skin, such as the palms of the hands and soles of the feet (Centers for Disease Control and Prevention (2021).

Localization-specific features:

• Face: Involvement of the eyes (risk of radiation cataracts) and the mucous membranes of the mouth and nose (radiogenic mucositis) should be considered in particular
• Male genitalia: risk of temporary or permanent infertility (control of FSH levels; early cryopreservation of sperm).

In contrast to burns, LRI (local radiation injury) and CRI (cutaneous radiation injury) develop over a longer period of time and involve periods of latency interrupted by active inflammation. Cutaneous radiation injuries heal slowly (not comparable to thermal injuries), the strength of the closed wound is lower and the pain associated with the injury is usually much more severe (Jose de Lima Valverde N et al. 2010). For equivalent doses of radiation, topography is a key factor in the severity and speed of onset of manifest radiation symptoms, with the face, chest and neck (areas with relatively thin skin) responding earlier and with more severe injuries than areas of the body with thicker skin, such as the palms of the hands and soles of the feet (Centers for Disease Control and Prevention 2021).

When assessing the severity of CRI, the energy of the radiation to which the skin has been exposed is the most important variable. The clinical signs of radiation injury vary depending on the dose and duration of exposure, but generally manifest themselves in several well-defined responses that may be spread over time. These include:

• Erythema (redness, similar to sunburn)
• Alopecia (hair loss due to follicle damage)
• Dry desquamation of the skin
• Moist desquamation of the skin (characterized by oozing/fluid loss)
• Local edema (swelling of the region where the CRI is located)
• Hyperpigmentation
• Atrophy of the skin
• Vascular damage with rarefaction of vessels
• Local telangiectasia
• Local fibrosis
• Ulceration
• Necrosis

In some cases, high radiation doses can also damage other, non-epithelial tissue, such as the underlying fat and muscle tissue. This complication can lead to an even worse prognosis for the patient in terms of healing and long-term prospects:

• Face: Involvement of the eyes (risk of radiation cataracts) and the mucous membranes of the mouth and nose (radiogenic mucositis) should be considered in particular.
• Male genitalia: risk of temporary or permanent infertility (control of FSH levels; early cryopreservation of sperm).

Patients may develop primary or transient erythema on the skin within a few hours after irradiation, related to changes in vascular permeability. The timing of the appearance of transient erythema has prognostic value. Early manifestations after exposure to ionizing radiation indicate higher absorbed doses in the tissue. Accordingly, the severity serves as a dose indicator. More severe clinical manifestations are observed in the following days or weeks.

The radiation effects observed in bones and skeletal muscles are predominantly late effects that occur months to years after radiation exposure (International Commission on Radiological Protection 2012). Radio-induced rhabdomyolysis and osteonecrosis are to be expected if the absorbed doses for muscles and bones are higher than ~40 Gy. CRI/LRI can persist for several months to years after radiation exposure in the form of recurrences (radiation-induced osteonecrosis is associated with severe chronic recurrences of CRI/LRI) (International Atomic Energy Agency 2018). The main feature of CRI/LRI is its dynamic evolution, with clinical manifestations progressing unpredictably even several years after the initial exposure.

Chernobyl: Characteristic cutaneous sequelae and associated clinical symptoms and diseases of 15 survivors of the Chernobyl accident with severe local exposure were systematically followed up by different groups between 1991 and 2000. Groups systematically followed up between 1991 and 2000. All patients showed cutaneous radiation syndrome (CRS) of varying severity, with xerosis, cutaneous telangiectasia and subungual splinter hemorrhages, hemangiomas and lymphangiomas, epidermal atrophy, disseminated keratoses, extensive dermal and subcutaneous fibrosis with partial ulceration, and pigmentary changes including radiation lentigo. Other radiation-related conditions such as dry eye syndrome (3/15), radiation cataract (5/15), xerostomia (4/15) and elevated FSH levels (7/15), which indicate impaired fertility, have also been documented (Iddins CJ et al. 2022).

1. Borthwick LA et al. (2013) Cytokine mediated tissue fibrosis Biochim Biophys Acta 1832:1049-1060.
2. Carvalho HA et al. (2018) Radiotherapy and immune response: the systemic effects of a local treatment Clinics (Sao Paulo) 73:e557s.
3. Centers for Disease Control and Prevention (2021). Cutaneous radiation injury (CRI): A fact sheet for clinicians. In: https://www.cdc.gov/nceh/radiation/emergencies/pdf/cri.pdf (ed), 2021.
4. de Andrade CBV et al. (2017) Radiotherapy-induced skin reactions induce fibrosis mediated by TGF-β1 cytokine Dose Response 15:1559325817705019.
5. Gordon S et al. (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32:593-604.
6. Gottlöber P et al. (2001) The outcome of local radiation injuries: 14 years of follow-up after the Chernobyl accident. Radiat Res 155:409-416.
7. Iddins CJ et al. (2022) Cutaneous and local radiation injuries. J Radiol Prot 42:10.1088/1361-6498/ac241a.
8. International Atomic Energy Agency (2018) The radiological accident in Chilca. In: IAEA (ed). Vienna, Austria, 2018.
9. International Atomic Energy Agency (2020). Medical Management of Radiation Injuries, Safety Reports. In: IAEA (ed). Series No 101. Vienna, Austria, 2020.
10. International Commission on Radiological Protection (2012). ICRP Statement on Tissue Reactions / Early and Late Effects of Radiation in Normal Tissues and Organs - Threshold Doses for Tissue Reactions in a Radiation Protection Context. In: ICRP (ed). ICRP Publication 118, 2012.
11. Jose de Lima Valverde N et al. (2010) An update on three radiation accidents in South America Health Phys 98:868-871.
12. Lewanski CR et al. (2001) Radiotherapy and cellular signaling. Lancet Oncol 2:366-370
13. Messerschmidt O et al. (1970) Radiation sickness combined with burn. Report SM-119/34. Vienna: International Atomic Energy Agency, 1970.
14. Pohlers D et al. (2009) TGF-β and fibrosis in different organs-molecular pathway imprints. Biochim Biophys Acta 1792:746-756.
15. Rachidi W et al. (2007) Sensing radiosensitivity of human epidermal stem cells Radiother Oncol 83:267-276
16. Reyes EH et al. (2016) Medical response to radiological accidents in Latin America and international assistance Radiat Res 185:359-365.
17. Schaue D (2017) A century of radiation therapy and adaptive immunity Front Immunol 8:431.
18. Schmuth M et al. (2001) Permeability barrier function of skin exposed to ionizing radiation Arch Dermatol 137:1019-1023.

19. Terasaki Y et al. (2011) Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress. Am J Physiol Lung Cell Mol Physiol 301:L415-L426.

20. Wick G et al. (2012) The immunology of fibrosis: innate and adaptive responses Trends Immunol 31:110-119.