Radiation-induced morphea L94.0

Radiation-induced morphea (RIM) is a rare but recognized late complication of radiotherapy. It was first described in 1905, not long after the discovery of X-rays by Roentgen. It was not until 1989 that radiation-induced morphea was recognized as a complication of radiotherapy for cancer (Gonzalez-Ericsson PI et al. 2018).

Radiation-induced morphea (RIM) is a rare and underestimated skin complication of radiotherapy - see also Cutaneous radiation syndrome and Chronic radiodermatitis.

The incidences are variously given as 1:500 - 1:3000 irradiated breast cancer patients (Bleasel NR et al. 1999; Friedman O et al. 2018). In comparison, the incidence of circumscribed scleroderma in the non-irradiated population is around 2.7/100,000 people per year (Ardern-Jones MR et al. 2003). Friedman et al. calculated a prevalence of 1:3000 in his collective of around 12,000 breast patients undergoing radiotherapy. To date, just over 100 cases of RIM have been described in the literature since this clinical picture was first described. The difference in the number of cases, also with regard to the published cases, suggests that radiotherapy should be classified as a risk factor. It can be assumed that there is a considerable number of unreported cases in the frequencies calculated in larger collectives of irradiated breast cancer patients.

The etiology of post-irradiation morphea is currently unknown, but age, total radiation dose, dose per fraction, number of fractions and degree of acute radiodermatitis do not appear to play a role. However, the risk appears to be higher in patients with connective tissue diseases, especially lupus erythematosus and scleroderma. Thanks to modern linear accelerators and techniques that achieve dose adjustment by modulating the intensity of the radiation beam, damage to the skin from radiotherapy is minimal. However, in the breast, skin and fat tissue are part of the irradiated volume as they are close to the irradiation field and become the target organ in post-mastectomy patients. This could be an explanation for the higher rate of morphea after breast irradiation.

A demonstrably increased expression of cytokines(interleukin-4, -5) and TGF-beta leads to an activation of fibroblasts and an increase in collagen synthesis (Smith KJ et al. 1997). TGF-beta induces an increased conversion of CD34-positive fibroblast precursor cells into myofibroblasts. This in turn leads to a thickening and sclerosis of the connective tissue. TGF-beta can stimulate its own synthesis through a positive feedback mechanism (Varga J et al. 2007).

The average age at diagnosis is 60 years (40-78), which is higher than that of idiopathic circumscribed scleroderma, which is 45 years. As a rule, the symptoms of RIM manifest themselves within one year after the end of radiotherapy, but both short and very long intervals, from one month to 32 years, have been described (Schaffer JV et al. 2000). It is also noteworthy that the vast majority of reports relate to adjuvant radiotherapy for breast cancer. The breast is the most common site, accounting for 88% of all reported cases. The remaining reported cases relate to the consequences of radiotherapy for head and neck cancer, endometrial cancer, vulva or lymphoma (Partl R et al. 2018). To date, there is no plausible explanation for this.

The lesions are generally described as well-demarcated, indurated plaques with varying degrees of erythema, usually localized to the irradiation site and extending to surrounding areas in 29% of cases. Three cases were described in which the lesions extended to distant sites: in one patient the lower leg was affected, in another the waist, groin, thigh and shin, and in a third the abdominal wall and both lower extremities; however, this patient had undergone radiotherapy for endometrial cancer prior to breast cancer.

The clinical appearance includes sclerosis of the skin and subcutaneous fatty tissue, usually limited to the radiation field, often accompanied by pain in this area, which can impair the patient's quality of life. Typically, after a variable period of asymptomatic latency, there is an abrupt appearance of flat, moderately painful, also pruritic edematous erythema (initial inflammatory phase), which progressively hardens over the course of a few weeks to months. The changes usually remain limited to the irradiated area, but can also spread beyond this area (Akay BN et al. 2010 ; Spalek M et al. 2015), in rare cases also generalize (Kushi J et al. 2011). The areolae mamillae remain unaffected by extensive sclerosis of the breast skin. Overlaps between morphea and lichen sclerosus have been described (Petersen E et al. 2018).

The diagnosis is made by biopsy. Histologically, dermal perivascular and interstitial inflammatory infiltrates are found in the inflammatory phase. In the sclerosing phase, there is a sclerotic restructuring of the tissue due to an increase in collagen. The epidermis remains uninvolved. In the inflammatory phase, an infection, a "radiation recall reaction" and an inflammatory tumor recurrence must be considered in the differential diagnosis. In the "burn-out phase", chronic radiodermatitis and associated post-radiogenic fibrosis are possible.

Numerous adverse skin reactions to radiotherapy have been described. RIM is often misdiagnosed as radiation-induced fibrosis. These two different diseases can be distinguished by their timing, clinical features and histopathologic findings. In the inflammatory phase, the differential diagnosis mainly includes erysipelas, radiation recall dermatitis and, above all, tumor recurrences (erysipelas-like skin metastases, carcinoma en cuirasse or carcinomatous mastitis). RIM tends to be a late complication with a sudden and abrupt onset. Histopathologic findings include inflammatory infiltrates of the skin. Radiation-induced fibrosis remains strictly localized. A biopsy is essential to differentiate between these diseases (Finnegan P et al. 2022).

There is no clear treatment regimen for this disease. The clinical outcome after therapy is often unsatisfactory. Commonly used methods and agents include: topical and systemic steroids, calcineurin inhibitors, systemic immunosuppressants including methotrexate, tacrolimus, heparin, hyaluronidase, phototherapy (UVA, UVA1, UVB, PUVA), systemic antibiotics, imiquimod, mycophenolate mofetil, photophoresis.

Alternatively, photodynamic therapy is proposed as a treatment option (Papanikolaou M et al. 2018). The review of the various treatment options in the largest RIM cohorts to date showed the best response to systemic treatment with MTX or ultraviolet B phototherapy (Fruchter R et al. 2017). Treatment should begin immediately after diagnosis at the inflammatory stage to prevent or delay irreversible fibrosis and atrophy.

RIM is a rarely described, serious and unpredictable late sequela with wide variability in timing of onset. Oncologists should consider this diagnosis early and perform appropriate tests to rule out infection, inflammatory cancer recurrence, radiation recall phenomenon, post-radiogenic fibrosis or chronic radiodermatitis.

1) Dr. Katja König / Fig1: 66 year old female patient, medication: Letrozole, RR-lowering agent, ASA 100, moderate nicotine abuse. Zn. n. Mamma-Ca right, BET, ax. SLNE, adjuvant radiotherapy over 6 weeks, 5x/week total 50 Gy/58.75 Gy, followed by slight erythema. Approx. three months later onset of increasing skin edema, prescription of lymph drainage and compression bra. Seven months later, full picture (see Fig. 1): brown hyperpigmentation, shiny, hardened skin with considerable sclerosis and shrinkage. Sono: tissue edema. MMG not possible due to lack of compressibility. Punch biopsy: fibrosis, vascular proliferate, hyperkeratosis, slight chronic inflammation. Inflammation, findings consistent with radiation dermatitis. In the meantime, antibiotic treatment with clindamycin as part of rehab for suspected mastitis, no improvement. Therapy trial with mometasone furoate cream topically over several weeks led to a clear improvement with fading of the hyperpigmentation and overall softer skin. Long-term goal: ablation and plastic reconstruction.

2) García-Arpa M et al. (2015): The patient was a 56-year-old woman diagnosed with infiltrating ductal carcinoma in the left breast that had been treated surgically. The results of the sentinel node biopsy were negative. The patient received adjuvant treatment consisting of chemotherapy, endocrine therapy with letrozole and external beam radiation therapy to the mammary gland with 6 and 18 MeV photons at a dose of 50 Gy, followed by boost radiation to the tumor bed at a dose of 66 Gy. The treatment was well tolerated. One year after completion of radiotherapy, a painful induration suddenly appeared in the left breast, which became smaller overall. Physical examination revealed asymmetry of both breasts and a well-defined, wood-like firm plaque with an erythematous border in the irradiated area. Biopsy revealed mild atrophy of the epidermis, hyperpigmentation of the basal layer, thickening of dermal collagen, loss of adnexal structures, and a discrete perivascular and interstitial lymphoplasmacytic inflammatory infiltrate that was both deep and superficial, with few interstitial eosinophils in the deep dermis. The immune status was normal and serologic testing for Borrelia was negative. Magnetic resonance imaging and mammography showed no abnormalities of the mammary gland. After treatment with oral prednisone at a dose of 0.5 mg/kg/d, which was reduced over two months, and topical treatment with clobetasol, the patient's pain disappeared and the induration and erythema subsided.

3) Gonzalez-Ericsson PI et al. (2018) A 44-year-old woman who had been successfully treated for triple-negative invasive breast cancer (TNBC) in the right breast complained of increasing pain, significant tenderness and itching in the right breast at a follow-up examination. Two years earlier, she had received neoadjuvant chemotherapy with cisplatin and paclitaxel for 12 weeks and subsequently underwent a right segmental mastectomy with oncoplastic reconstruction. A complete pathologic response was achieved in the breast and the six axillary sentinel lymph nodes examined. She underwent subsequent adjuvant chemotherapy with four cycles of Adriamycin and cyclophosphamide, followed by external beam radiotherapy of the right breast and axilla with a total dose of 50 Gy over 28 fractions in 49 days, without boost. She did not experience any major acute side effects. Fifteen months after completion of radiotherapy, physical examination revealed that the skin of all four quadrants of the right breast, except the areola, was sclerotic and contracted, with marked thickening and diffuse pink discoloration accentuated by a purplish-pink cliff-like border. Mammography and magnetic resonance imaging (MRI) showed diffuse thickening of the breast skin and no focal abnormalities. To rule out a recurrence or a new malignancy, two punch biopsies of the right breast skin were taken. These showed pronounced sclerosis of the skin. The epidermis showed slight orthokeratosis, but was otherwise unremarkable. The mid and deep reticular dermis was dilated with thickened and swollen, tightly compacted collagen bundles. A superficial and deep perivascular and periadnexal lymphocytic infiltrate with occasional plasma cells and conspicuous atrophy of the adnexal structures with marked loss of surrounding adipose tissue were present. The dermal lymphatic vessels showed slight dilatation but were still normally distributed.

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