Radiation port cutaneous metastases: reports of two patients whose recurrent visceral cancers presented as skin lesions at the site of previous radiation and literature review.

Radiation therapy is associated with a variety of complications, including the development of primary skin cancers in the radiated region. However, it is rare for patients with visceral cancers who are treated with radiation therapy to subsequently develop cutaneous metastasis within the radiation port. We describe two patients with internal malignancies who developed cutaneous metastases within their radiation ports following radiotherapy. In addition, we used PubMed to perform an extensive literature review and identify additional reports of cutaneous metastasis within a radiation port. We excluded patients who developed melanoma or primary skin cancers in the radiation port. We also excluded patients with non-solid organ malignancies. Herein, we summarize the characteristics of 23 additional patients who experienced radiation port cutaneous metastases and explore possible mechanisms for the occurrence of radiation port cutaneous metastases.

What was known?

Radiation is frequently used in cancer treatment, and is associated with a variety of local and systemic adverse effects.

Cutaneous effects of radiation therapy include dermatitis, erythema multiforme, hyperpigmentation, poikiloderma, and primary non-melanoma skin cancers.

Visceral cancers metastasize to the skin in about 5% of patients, and cutaneous metastases often signify advanced disease with poor prognosis.

Introduction

The skin may be the site of metastasis of visceral cancers. In a meta-analysis of 20,380 patients with metastatic cancer, Krathen et al. found that 5.3% (1,080 of these individuals) developed cutaneous metastasis.[1] Radiation therapy is often used in the treatment of internal malignancies.[2] Radiation typically affects the skin within the radiation port; however, it is rare for the primary cancer to metastasize within the irradiated skin.[34567891011121314151617171819202122] We describe two patients who developed cutaneous metastases in the area previously irradiated for treatment of their primary malignancies. Additionally, we summarize the characteristics of other patients who developed cutaneous metastases within their radiation ports.

Case Reports

Case 1

A 65-year-old man with a history of squamous cell carcinoma of the anal canal presented in February 2011 with newly formed nodules on his scrotum. The patient had been diagnosed with cancer of the anal canal in September 2010 and was treated with chemotherapy (5-fluorouracil and cisplatin) and concurrent radiation. His radiation therapy was delivered in 29 2 Gy fractions over 38 days for a total of 58 Gy. His treatment was completed on November 4, 2010. During his therapy, he developed severe radiodermatitis which subsequently resolved completely.

In January 2011, he discovered several new skin lesions on his scrotum [Figures 1 and 2]. Cutaneous examination revealed eight painless nodules on his right scrotum, and two additional nodules on his right inguinal fold. All of the new lesions were restricted to the area within his radiation port. They were mildly pruritic; one had ruptured and extruded foul-smelling white material. Biopsies from both sites showed metastatic squamous cell carcinoma, indicating loco-regional failure of his chemoradiation therapy.

Figure 1

Recurrent metastatic anal canal squamous cell carcinoma presenting within the radiation port as multiple nodules on the right scrotum

Figure 2

(a and b) Closer views of the right scrotum shows the cutaneous metastases located in the area of radiotherapy

Restaging chest roentgenogram and computerized axial tomography scan also discovered lung metastases. The patient was sequentially treated with several different antineoplastic agents either as single or combination drug therapy. However, there was not only increased size of previous scrotal nodules but also continued appearance of new cutaneous metastases. He was referred to the Phase 1 department to be considered for a trial of an investigational drug treatment.

Case 2

A 52-year-old woman was diagnosed in February 2009 with invasive ductal carcinoma in her left breast and poorly differentiated carcinoma in her right breast. She was subsequently treated with neoadjuvant chemotherapy consisting of four cycles of doxorubicin and cyclophosphamide. Following her initial chemotherapy, she received weekly paclitaxel for 12 weeks and trastuzumab every 3 weeks for 1 year.

In October 2009, the patient underwent modified radical mastectomy of the left breast and right lumpectomy with axillary lymph node dissection. She began radiation therapy in December 2009. This included bilateral radiation of the chest wall, internal mammary nodes, supraclavicular fossa, and axillary apex totaling 50 Gy in 25 fractions. In addition, her left infraclavicular fossa received 10 Gray in 5 fractions, and her mastectomy and lumpectomy scars were boosted with an additional 14 Gray in 7 fractions. In February 2010, she was restaged and considered to be free of cancer.

Cutaneous examination in August 2011 revealed macular erythema with pruritic, erythematous macules, superficial plaques, and small papules within the radiation port on the left chest wall [Figures 3 and 4]. She also had a nonpruritic, hyperpigmented superficial plaque with surrounding areas of erythema within the radiation port on the right breast [Figures 3 and 5]. The skin lesions had appeared 1 month earlier and had not improved with over-the-counter topical preparations applied by the patient. Biopsy of both areas revealed metastatic breast carcinoma.

Figure 3

Recurrent metastatic breast carcinoma presented within the radiation ports of the left chest and right breast

Figure 4

(a) Distant and (b and c) closer views of radiation port cutaneous metastases of breast cancer on the left chest presenting as (b) erythematous papules and plaques and (c) macular erythema

Figure 5

(a) Distant and (b) closer views of right breast radiation port in which recurrent cutaneous metastatic breast cancer presents as a hyperpigmented plaque with surrounding erythema

Discussion

Radiation therapy is an integral modality in the treatment regimen of oncology patients.[2] High-energy electromagnetic radiation (in the form of X-rays, gamma rays, or electron beams) is used to damage nuclear deoxyribonucleic acid (DNA) of rapidly dividing cells, thereby blunting further cell proliferation.[23] Radiotherapy can also be administered by implanted or injected sources of radioactivity.[23] Because cancer cells proliferate more rapidly than somatic cells, they are more susceptible to the effects of radiation therapy.[23]

The potential toxicities of radiation can be significant, however, the benefits of radiotherapy often outweigh the risks.[21] In addition, the quality of the radiation source and the treatment techniques are constantly improving, allowing better delivery to the target organ while minimizing the effects on the surrounding tissue.[24]

Cutaneous effects of radiation therapy can include not only acute dermatitis and chronic skin changes such as hyperpigmentation and poikiloderma,[24] but also several other conditions such as acne,[25] blistering disorders,[26] epilation,[2327] erythema multiforme,[28] fungal infections,[29] graft-versus-host disease,[30] lichen planus,[252631] radionecrosis,[32] and scleroderma.[27] Radiotherapy has also been shown to predispose individuals to subsequent development of primary, predominantly non-melanoma, skin cancers in the radiation port.[3334] Much less commonly, treatment with radiation may subsequently be associated with the appearance of metastasis from the treated internal malignancy to the radiated skin.

Cutaneous metastasis within a radiation port is a rare occurrence.[3] We performed an extensive review of the literature available on PubMed using the following search criteria: Cutaneous or skin, metastasis or metastases, radiation or irradiation, and not melanoma or sarcoma or basal cell. We excluded patients who developed melanoma or other primary skin cancers within their radiation port. We also excluded those who developed benign tumors or non-solid organ tumors in the previously radiated region. To the best of our knowledge, radiation port cutaneous metastasis from visceral malignancies has only been described in 25 patients [Table 1]. The majority of the patients (88%) were women. Only three men, who had either carcinoma of the breast, anal canal, or stomach, have been described with radiation port cutaneous metastases.

Table 1

Characteristics of patients with cutaneous metastases of original tumor in radiation ports [a,b]

The breast was the most common site of primary neoplasm, accounting for 59% (17 individuals) of these patients. Other locations of primary tumors included the female genital organs [such as the cervix (two individuals), uterus (two individuals), and vulva (one individual)], anal canal (one individual), nasopharynx (one individual), and stomach (one individual). The patients ranged in age from 35 years to 70 years (mean = 54 years, median = 55 years) when their primary malignancy was originally diagnosed.

The average time between diagnosis of the primary tumor and the appearance of cutaneous metastases was 24 months (range: 3 to 66 months, median = 19 months). This duration of time is similar to that observed in oncology patients who develop cutaneous metastases that were not confined to (or originated within) their radiation port.[35]

The mean survival for cancer patients who developed cutaneous metastases, based upon the findings from two major reviews (which included 20,380 patients and 7,316 patients), was 1 year.[35] Similar to the observations from these studies, the prognosis for patients who develop cutaneous metastasis within their radiation port is also poor. Their median survival, after discovery of their cutaneous metastasis, was 6 months and patient survival ranged from 1 month to 1 year.

It is widely accepted that localized insults to the skin can make that region more susceptible to disease and infection. In 1995, Wolf et al. described a phenomenon in patients with previous herpes zoster infection who subsequently developed tumors at the site of their original viral infection. He coined the term “isotopic response” to describe “the occurrence of a new skin disorder at the site of another, unrelated, and already healed skin disease”, however, his definition excluded exogenous damage, such as that occurring from radiation, as the etiology of initial skin injury.[36] Subsequently, Shurman et al. expanded on Wolf et al.'s concept by recommending the use of the term “isoradiotopic response” to refer to dermatoses arising within a radiation port.[26]

Ruocco et al. have postulated a mechanism of pathogenesis for the isotopic and isoradiotopic response. They suggested that cutaneous disease or injury (including ionizing radiation) can impair lymph drainage and alter neuromediator signaling. These changes result in an “immunocompromised district” that is particularly susceptible to infections, tumors, or immune disorders.[37] In addition, dysregulation of cytokines has been implicated in the development of a radiation-induced immunocompromised district.[38] Finally, others postulate that radiation-induced damage to endothelial cells leads to trapping of tumor cells and enhances the occurrence of metastasis.[3] Studies done in animals have demonstrated increased metastasis in tissue that was previously irradiated.[3]

Conclusion

Cutaneous metastasis within a radiation port is rare. Recurrent tumor metastases, localized to previously irradiated skin, have been observed in 25 patients. This phenomenon occurred most frequently in women in whom radiotherapy was a component of the management of their primary breast cancer. Less frequently, radiation port cutaneous metastases have been noted in patients with neoplasms originating in the female genital organs, the anus, the nasopharynx, and the stomach. The appearance of radiation port cutaneous metastases was noted as early as 1-3 months, and as long as 6 years, following completion of radiotherapy; however, the mean duration of time between the diagnosis of the patient's primary cancer and the discovery of their radiation port cutaneous metastases was 24 months. We speculate that an “immunocompromised district” created by the radiation therapy may facilitate the spread of malignant cells to the previously radiated skin, which we refer to as radiation port cutaneous metastases.

What is new?

Radiation port cutaneous metastasis is a rare complication associated with treatment of internal malignancies with radiation therapy. This may represent an “isoradiotopic response.”

The breast is the most common site of primary malignancy that subsequently metastasizes to the previously radiated skin.

Prognosis for patients who develop radiation port cutaneous metastasis is poor (median survival of 6 months).