- Email: [email protected]
Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study
Clinical Oncology xxx (2018) 1e7 Contents lists available at ScienceDirect
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Original Article
Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study M. Lutsyk *, R. Ben-Yosef *y, R. Bergman yz, A. Kuten yx, G. Bar-Sela *y * Division
of Oncology, Rambam Health Care Campus, Haifa, Israel Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel z Department of Dermatology, Rambam Health Care Campus, Haifa, Israel x Department of Oncology, Italian Hospital, Haifa, Israel y
Received 13 February 2018; received in revised form 3 May 2018; accepted 22 May 2018
Abstract Aims: To determine the role of total skin electron irradiation (TSEI) as a cause of second malignancies in mycosis fungoides patients. Materials and methods: Mycosis fungoides patients referred to TSEI were followed in a longitudinal study. Other diagnosed malignancies were obtained after cross-matching with the Israel National Cancer Registry database. Results: Between 1974 and 2010, 197 patients were treated: 134 (68%) men, 63 (32%) women; mean age 58 17years. Topical/systemic treatment was given to 134 (68%) patients. TSEI was given to 104 (68.9%) patients. Seven (4.6%) received sub-TSEI and 40 (26.5%) received focal electron irradiation fields. Forty-six (23%) patients did not receive radiotherapy. The second primaries rate was 6.7 times higher in male mycosis fungoides patients and 13.1 times higher in female mycosis fungoides patients than in the general Israeli population. Malignant melanoma developed in eight patients after radiotherapy, in one patient without irradiation. The skin-related cancer rate after irradiation versus no irradiation was higher (P ¼ 0.018). Combination radiotherapy with psoralen þ ultraviolet A and/or nitrogen mustard yielded 11 cases of skin cancer versus no cases without irradiation. Conclusions: Mycosis fungoides patients have a high incidence of sequential malignancies. TSEI is associated with higher ‘skin-related cancer’ rates. Close longitudinal follow-up of mycosis fungoides patients is obligatory. Ó 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Key words: Longitudinal study; mycosis fungoides; sequential malignancies; skin electron beam radiotherapy; skin-related cancers
Introduction The extra-nodal T-cell lymphoma with predominant skin involvement, also known as mycosis fungoides, has low incidence with different world distribution rates [1e4]. The prognosis depends on the stage at presentation and varies from indolent, well-controlled with topical drugs to a very aggressive form with high mortality rates (Sezary syndrome) [5,6]. Medical treatment options are numerous and include skin-directed or systemic therapies and their combinations with different effectiveness for each method [7,8]. For decades, total skin electron beam irradiation (TSEI) has
Author for correspondence: G. Bar-Sela, Division of Oncology, Rambam Health Care Campus, POB 9602, Haifa 31096, Israel. Tel: þ972-4-7776409; Fax: þ972-4-7776427. E-mail address: [email protected] (G. Bar-Sela).
been considered as the most efficient approach to bring longstanding remission [9e12]. With long-lasting response to TSEI, however, there is an increasing risk of developing second primary malignancies. This phenomenon was described in several reports, illustrating that mycosis fungoides patients may suffer from other types of lymphoma or solid tumour, whether or not they were treated with radiotherapy [11,13e17] and speculation about the mycosis fungoides patient’s genotype as the underlying cause has been raised. The follow-up period for mycosis fungoides patients may continue for decades and, therefore, longitudinal prospective studies are extremely difficult, given the low incidence of the disease. This retrospective study describes and evaluates the rate of second malignancies in patients with mycosis fungoides referred to skin irradiation in one national centre dedicated to TSEI for 40 years. The purpose of the study was to determine the role of TSEI as
https://doi.org/10.1016/j.clon.2018.06.006 0936-6555/Ó 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006
2
M. Lutsyk et al. / Clinical Oncology xxx (2018) 1e7
the underlying cause of second malignancies in mycosis fungoides patients.
Patients and Methods Data Collection The study included retrospective data of all patients who were referred to Rambam Health Care Campus (RHCC) in Haifa, Israel for skin electron beam irradiation (SEI) from 1974 to 2010. Patients’ personal medical records were collected from hardcopy medical reports until 1990 and then from computerised records.
standardisation according to the Segi standard population [24]. The calculated age-standardised rate (ASR) (per 100 000 person-years) of malignancies within mycosis fungoides patients was compared with the ASR in the Israeli population updated to February 2016 (open web access). Differences in skin cancers between radiotherapy and non-radiotherapy patient groups were tested using the chisquared test. Data reported to the INCR on squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) were included only in the calculation for skin cancers and not for whole second malignancies due to possible unreported cases. Statistical analyses were carried out using SPSS 21.0 software for Windows.
Staging
Results In accordance with the last version of the TNM v7 staging system [18], all diseases were restaged based on description and images stored in the medical records and databases existing in RHCC. The study included all patients with stages mycosis fungoides IeIV. Epidemiological Data The final mycosis fungoides patient list was matched to the Israeli National Cancer Registry (INCR) data [19]. The INCR was asked for all malignancies registered in the study population. After strict authorisation procedures, the needed information was obtained and updated at the end of February 2016. Treatment before Radiotherapy Skin-directed cotherapeutic agents, narrow band ultraviolet B radiation (NBUVB), psoralen and ultraviolet A radiation (PUVA) and systemic interferon were used before referring the patients to the radiation unit in RHCC. Radiation Therapy Techniques and Doses The radiotherapy technique for TSEI used from 1970 until 1992 was the modified Christie Hospital translational technique described by Anacak et al. [20]. Since 1992, the six-dual Stanford technique has been used [21,22]. The delivered doses changed in accordance with published evidence from 36 Gy in 4 Gy one weekly fraction to 30 Gy in 1.2 Gy fractions for 5 days a week [23]. Several patients were treated with total body irradiation (TBI) of 1.25 Gy in 0.25 Gy fractions a week before and after TSEI [20]. The tumoural lesions required boosts in some cases. If skin lesions did not cover more than 10% of the body surface, subtotal or focal SEI only was used. Statistics The study protocol was created as for a retrospective cohort. Male and female mycosis fungoides patients were distributed to 16 age groups using the direct method of
Between 1974 and 2010, about 300 patients were referred to the RHCC Radiation Unit. Hardcopy and electronic data were kept for 197 patients: 134 (68%) men and 63 (32%) women. The rest of the medical records were not included due to logistical issues, with no selective criteria, which could have caused a bias. Among the patients were four children, ranging in age from 2 to 19 years, mean 10 7 years. The mean adult age was 58 17 years. The median observation time was 5.42 years and the maximum period of observation was 44 years (0.5e47 years). One hundred and thirty-four (68%) patients received topical or systemic treatment with one or several of the following agents: nitrogen mustard, NBUVB, PUVA, cotherapy (e.g. methotrexate) or immunotherapy (e.g. interferon). The whole group included 151 (77%) patients who were treated with radiotherapy (radiotherapy group) and 46 (23%) patients who were referred to radiotherapy, but did not receive the treatment for various reasons (nonradiotherapy group) (Table 1). Among the patients who received radiotherapy, 104 (68.8%) patients were treated with the TSEI approach and the mean delivered dose was 30.8 5.8 Gy. Seven patients were treated with subtotal SEI, with a mean dose of 31.46 6.18 Gy; 40 patients (26.5%) received focal electron irradiation field, with a mean dose 31.51 5.84 Gy. Four of Table 1 Patient characteristics Total number of patients Males (%) Females (%) Mean adult age, years (%) Mean child age, years (%) Treated with radiotherapy (%) Referred but not treated with radiotherapy (%) Pre-treated before radiotherapy (e.g. nitrogen mustard, NBUVB, PUVA, cotherapy or immunotherapy)
197 134 (68) 63 (32) 58.0 3 17.1 (98) 10 7 (2) 151 (77) 46 (23) 134 (68)
NBUVB, narrow band ultraviolet radiation; PUVA, psoralen þ ultraviolet A treatment.
Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006
M. Lutsyk et al. / Clinical Oncology xxx (2018) 1e7
151 patients in the radiotherapy group were treated with TBI at a dose of 1.25 Gy. Fifteen patients with mycosis fungoides relapse after TSEI were treated with radiotherapy: three patients with another course of TSEI (2%, mean dose 20 4.5 Gy), one patient with subtotal SEI (16 Gy), and 11 patients with focal electron beam irradiation (7.2%, mean dose 17 7.4 Gy). Of the nine (6%) patients who relapsed after non-TSEI, four were treated with TSEI (2.7%, mean dose 30 6.3 Gy) and five patients received non-TSEI (3.3%, mean dose 29.3 5.8 Gy). Demographic data on the incidence of cancer in the Israeli population published in 2016 reported incidences of: Jewish males 385.77, Jewish females 462.63, Arabic males 152.17 and Arabic females 161.53 cases per 100 000 persons. INCR data do not include incidences of BCC and SCC of the skin after 2007 [25,26]. Using the data and crude cancer incidence, the incidence without BCC and SCC among mycosis fungoides patients was compared with the cancer incidence of the whole population. After cross-matching the RHCC data with INCR data, 82/197 (41.6%) patients had other malignancies. Among the 151 patients in the radiotherapy group, 64 (42.4%) had additional oncological and/or haematological malignancies, whereas 18 cases of 46 patients (39.1%) in the non-radiotherapy group were registered (Table 2). Table 2 shows the profile of malignancies that appeared in both groups. The most frequent solid tumours in the radiotherapy group were non-melanoma skin malignancies, malignant melanoma, gastrointestinal and genitourinary tumours and Kaposi’s sarcoma. Lymphomas (Hodgkin and non-Hodgkin types) were registered as the main haematological malignancies. Among patients in the nonradiotherapy group, the most frequent solid tumours were genitourinary tumours, breast cancer and non-melanoma skin malignancies. Non-Hodgkin’s lymphomas were the most frequent haematological malignancies in this group as well. There was no statistical significance between the
3
groups in the incidence of total solid and haematological malignancies (P ¼ 0.86). In most of the patients, second malignancies appeared after the diagnosis of mycosis fungoides. In the radiotherapy group of 151 patients, 42 had second primaries. Of these, 13 had third primaries; fourth primaries were found in two of those 13. Among the 46 patients in the nonradiotherapy group, 12 had second primaries, four of whom had third primaries; one of those four had a fourth primary. However, in 22 of the 151 patients treated with radiotherapy, mycosis fungoides was diagnosed as a second primary; in three of those 22, mycosis fungoides was the third malignancy in chronological order. Also, in six of the 46 patients who were not treated with radiotherapy, mycosis fungoides was the second malignancy; in one of those six, mycosis fungoides was the third malignancy. In total, 64 patients in the radiotherapy group developed 82 other malignancies, whereas 18 patients in the nonradiotherapy group developed 24 malignant diseases (Table 3). The ASR of sequential malignancies for all age groups was calculated. The incidence of second primaries in male mycosis fungoides patients was 6.7 times higher than in the general male Israeli population; the incidence of second primaries in female mycosis fungoides patients was 13.1 times higher than in the general female Israeli population. In male mycosis fungoides patients, the rate was increased after 40 years of age, with peaks at ages 50, 60 and 75 years. In female mycosis fungoides patients, the increased rate was observed in four peaks at ages 25, 40, 55 and 75 years. The rates in men and women were similar and higher than in the general Israeli population after 60e65 years of age (Figure 1). The curves of male and female malignancy rates among mycosis fungoides patients climb after age 40e49 years, whereas the Segi standardised world population curve goes down, crossing at the same ages.
Table 2 Type of sequential malignancies among mycosis fungoides patients Site or type of malignancy
Radiotherapy patients (total n ¼ 151)
Non-radiotherapy patients (total n ¼ 46)
Lymphoma (non-mycosis fungoides type) Merkel’s cell carcinoma Gastrointestinal malignancies Genitourinary malignancies Kaposi’s sarcoma Breast malignancies Melanoma Gynaecological malignancies Thyroid malignancies Brain malignancies Endocrine malignancies Leukaemia Lung malignancies Parotid malignancies Sarcoma Unknown primary carcinoma
19 (12.6%) 1 (0.7%) 7 (4.6%) 6 (4.0%) 5 (3.3%) 3 (2.0%) 8 (5.3%) 2 (1.3%) 2 (1.3%) 2 (1.3%) 2 (1.3%) 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)
6 0 1 7 0 3 1 1 1 0 0 1 1 0 0 0
(13%) (2.2%) (15.2%) (6.5%) (2.2%) (2.2%) (2.2%)
(2.2%) (2.2%)
Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006
4
M. Lutsyk et al. / Clinical Oncology xxx (2018) 1e7
Table 3 Appearance of malignancies among mycosis fungoides patients
Radiotherapy group Non-radiotherapy group Total
Patients (n)
Mycosis fungoides patients, without second malignancies n (%)
Mycosis fungoides patients with other malignancies n (%)
Total number of other cancer diagnoses
151 46 197
87 (57.6) 28 (60.8) 115 (58.4)
64 (42.4) 18 (39.1) 82 (41.6)
82 24 106
Four patients were treated with TBI. In three patients, TBI preceded TSEI treatment. All three had a second malignancy and two had a third primary. No additional malignancy was registered in the patient who had only TBI. No sequential malignancies were found in the subgroup of four children. Skin Cancers In the radiotherapy group, eight patients had a malignant melanoma. One had acral lentiginous, two had superficial spreading, three had in situ melanomas and two had invasive melanomas. All patients received TSEI. In the nonradiotherapy group, only one patient had invasive melanoma. In the radiotherapy group, one patient with malignant melanoma was also treated with TBI. Kaposi’s sarcoma was diagnosed in five patients from the radiotherapy group. In the radiotherapy group, 33 cases of all types of invasive and non-invasive skin cancer (malignant melanoma,
Merkel’s cell carcinoma, Kaposi’s sarcoma, SCC, BCC) were diagnosed, compared with only three cases in the nonradiotherapy group. The incidence of skin-related cancers due to SEI was statistically higher in patients in the radiotherapy group (P ¼ 0.018). As previous treatments with PUVA and/or nitrogen mustard have cancerogenic potential and may be considered as a risk factor for skin cancer, their use in the study population is shown in Table 4. In the radiotherapy group, the combination of these two agents and electron beam irradiation of skin added somewhere in the course of treatment resulted in two (5%) skin cancer cases among 39 (26%) patients who received PUVA treatment, eight (21%) skin cancer cases among 16 patients treated with nitrogen mustard and one (3%) case of skin cancer of 13 patients after combination PUVA and nitrogen mustard. In the non-radiotherapy group, no skin cancer was registered, although 15 patients received PUVA, five patients received nitrogen mustard and two patients both.
Fig 1. Secondary malignancies in mycosis fungoides (MF) patients and rate of malignancies in the Israeli population (age-standardised ratio calculated for both). Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006
M. Lutsyk et al. / Clinical Oncology xxx (2018) 1e7
5
Table 4 Skin cancer after skin-directed agents in combination with radiotherapy Skin-directed agents
Radiotherapy group, Total n ¼ 151
No radiotherapy group, Total n ¼ 46
Patients n (%)
Skin cancer cases (%)
Patients n (%)
Skin cancer cases
NBUVB, PUVA Nitrogen mustard NBUVB, PUVA, nitrogen mustard
39 (26%) 16 (11%) 13 (9%)
2 (5%) 8 (21%) 1 (3%)
15 (33%) 5 (11%) 2 (4%)
0 0 0
NBUVB, narrow band ultraviolet radiation; PUVA, psoralen þ ultraviolet A treatment.
Discussion As the only national dedicated centre for SEI applied to mycosis fungoides patients in Israel, we have followed our patients for 42 years. To the best of our knowledge, the current report has the longest follow-up period ever reported in the literature. Using the INCR service, we have observed longitudinally and, in some cases, for a lifetime, the development of sequential tumours in persons suffering from mycosis fungoides [14]. Given the absence of differences in the incidence of sequential tumours between radiotherapy and non-radiotherapy groups, we believe that TSEI is not the only factor in the development of second malignancies [27e29] A new study with more patients from many centres, combined with a web-based database for a long-term observation period, may provide wider answers to this question. The high incidence of solid cancers and/or haematological malignancies may be explained by an intrinsic defect in the immune system response to the appearance of cancer cells within solid tissue or blood. It was reported that mycosis fungoides patients have other types of lymphoma or solid tumour [14,30,31]. The structure of second tumour morbidity presents a wide spectrum of malignancies, pointing at multiple defects explaining the sequential tumour appearing in both irradiated and unirradiated patients. The most frequent malignancy among mycosis fungoides patients is haematological, as shown in several studies [17,32,33]. The incidence of solid tumours was reviewed in studies from several centres and revealed a higher age-specific standardised population ratio (ASR) among mycosis fungoides patients who received radiotherapy or not [14,28,27,34]. The current study confirms those results. Consideration of causes and triggers launching an oncogenesis in different tissues in mycosis fungoides patients is beyond the scope of the current discussion. However, some notes are worth making. Topical application of nitrogen mustard in some patients may cause the development of malignant melanoma [35]. Eight cases of malignant melanoma were found in the radiotherapy group and in one case in the non-radiotherapy group. All nine cases of melanoma in mycosis fungoides presented a higher incidence than in the Israeli population [36]. The number of patients with melanoma was higher in the group following TSEI. PUVA treatment was reviewed in the late 1980s. The benefits and risks of its combination with other skin-
directed topical agents were studied in several large trials (e.g. a nationwide cohort study from Denmark) [37]. Several studies concluded that the combination of ultraviolet, psoralen and ionising radiation may increase ‘the expression of skin cancer’ [11,38e40]. In the current study, we considered all ‘skin-related cancers’ as one group. Although the skin cancers differed in their prognosis, they all represented a significant illness reported to the Israeli Cancer Registry [25]. Superficial BCC and SCC of the skin are not reported to the Registry [26]. Those reported and included in the current analysis represent more significant tumours that cause patient referral to oncology treatment. Although data on superficial BCC and SCC are missing, the conclusion of elevated skin-related cancers after skin irradiation can be defined based on the current data and a ‘causeeeffect’ correlation can be established. The risk of developing a second primary after radiation exposure is elevated independent of the type of radiotherapy modality [41]. Specific data on the influence of electron beam skin irradiation on second primary development are scarce and do not provide the underlying mechanism to explain the oncogenesis [42], although the ‘bystander effect’ on deep layers of skin may partly explain it. The influence of irradiation on the microenvironment of unirradiated skin cells results in abnormal extracellular signalling causing diminished abnormal cell suppression [43]. The process involves many factors, such as disturbances in cell adhesion, tumour suppressor p53 and response to radiation stress of transforming growth factor b1 (TGFb1) functioning, and stroma cell changes that eventually contribute to neoplastic progression [43e46]. Sparing of normal tissue volume is a primary concept of intensity-modulated radiation therapy [47]. However, in the case of mycosis fungoides, the skin is the main organ ‘targeted’ by disease and, therefore, TSEI is a whole organ irradiation that narrows the therapeutic window due to giving of a biologically effective dose escalation without minimising normal skin toxicity [23]. One toxicity type is a second malignancy development [22], as reported in the current study.
Conclusions Mycosis fungoides patients have a high incidence of sequential malignancies in almost every system of the human body, not related to skin irradiation. Nevertheless,
Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006
6
M. Lutsyk et al. / Clinical Oncology xxx (2018) 1e7
electron skin irradiation is associated with a higher incidence of ‘skin-related cancers’ among these patients. This observation should be included in the ‘patient informed consent’ before skin irradiation. Due to the retrospective data collection, some interesting points, such as areas of re-irradiation and sites of SCC or BCC appearance, exact surface area of focal irradiation or detailed on-treatment skin toxicity assessment, cannot be clarified.
Acknowledgement Thank you to the Israel National Cancer Registry for linking our patient cohort to the registry database for the purpose of identifying second primary malignancies.
[13]
[14]
[15] [16]
[17]
References [1] Weinstock MA, Gardstein B. Twenty-year trends in the reported incidence of mycosis fungoides and associated mortality. Am J Public Health 1999;89:1240e1244. [2] Beltran B, Morales D, Quinones P, Salas R, Carrasco-Yalan AA. Distribution and pathology characteristics of non Hodgkin lymphoma in Peru: a study of 1014 cases using WHO classification of lymphoid neoplasm. Blood ASH Annu Meet Abstr 2007;110:4419. [3] Sukpanichnant S, Sonakul D, Piankijagum A, Wanachiwanawin W, Veerakul G, Mahasandana C, et al. Malignant lymphoma in Thailand: changes in the frequency of malignant lymphoma determined from a histopathologic and immunophenotypic analysis of 425 cases at Siriraj Hospital. Cancer 1998;83: 1197e1204. [4] Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973e2002. Arch Dermatol 2007;143:854e859. [5] Weinstock MA, Horm JW. Population-based estimate of survival and determinants of prognosis in patients with mycosis fungoides. Cancer 1988;62:1658e1661. [6] Kim YH, Bishop K, Varghese A, Hoppe RT. Prognostic factors in zary syndrome. erythrodermic mycosis fungoides and the Se Arch Dermatol 1995;131:1003e1008. [7] Kaye FJ, Bunn Jr PA, Steinberg SM, Stocker JL, Ihde DC, Fischmann AB, et al. A randomized trial comparing combination electron-beam radiation and cotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 1989;321:1784e1790. [8] Bagherani N, Smoller BR. An overview of cutaneous T cell lymphomas. F1000Res 2016;5. https://doi.org/10.12688/ f1000research.8829.1. [9] Le Bourgeois JP, Haddad E, Marinello G, Marin L, Mazeron JJ, Ganem G. The indications for total cutaneous electron beam radiation therapy of mycosis fungoides. Int J Radiat Oncol Biol Phys 1987;13:189e193. [10] Tadros AA, Tepperman BS, Hryniuk WM, Peters VG, Rosenthal D, Roberts JT, et al. Total skin electron irradiation for mycosis fungoides: failure analysis and prognostic factors. Int J Radiat Oncol Biol Phys 1983;9:1279e1287. [11] Stein ME, Anacak Y, Zaidan J, Drumea K, Gez E, Bar-Deroma R, et al. Second primary tumors in mycosis fungoides patients: experience at the Northern Israel Oncology Center (1979e2002). J Buon 2006;11:175e180. [12] Chinn DM, Chow S, Kim YH, Hoppe RT. Total skin electron beam therapy with or without adjuvant topical nitrogen
[18] [19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys 1999;43: 951e958. Huang KP, Weinstock MA, Clarke CA, McMillan A, Hoppe RT, Kim YH. Second lymphomas and other malignant neoplasms in patients with mycosis fungoides and Sezary syndrome: evidence from population-based and clinical cohorts. Arch Dermatol 2007;143:45e50. Kantor AF, Curtis RE, Vonderheid EC, van Scott EJ, Fraumeni Jr JF. Risk of second malignancy after cutaneous Tcell lymphoma. Cancer 1989;63:1612e1615. Barzilai A, Trau H, David M, et al. Mycosis fungoides associated with B-cell malignancies. Br J Dermatol 2006;155:379e386. Hallermann C, Kaune KM, Tiemann M, Kunze E, Griesinger F, Mitteldorf C, et al. High frequency of primary cutaneous lymphomas associated with lymphoproliferative disorders of different lineage. Ann Atol 2007;86:509e515. Hodak E, Lessin S, Friedland R, Freud T, David M, Pavlovsky L, et al. New insights into associated co-morbidities in patients with cutaneous T-cell lymphoma (mycosis fungoides). Acta Derm Venereol 2013;93:451e455. https://doi.org/10.2340/ 00015555-1496. AJCC cancer staging atlas. New York: Springer; 2012. https:// doi.org/10.1007/978-1-4614-2080-4. National Cancer Registry, Ministry of Health. Available at: https:// www.health.gov.il/English/MinistryUnits/HealthDivision/Icdc/ Icr/Pages/default.aspx. [Accessed 21 February 2017]. Anacak Y, Arican Z, Drumea K, Rosenblatt E, Tamir A, Chetver L, et al. Total skin electron irradiation in mycosis fungoides: comparison between a modified Christie Hospital translational technique and the Stanford technique. Leuk Lymphoma 2002;43:2093e2097. Hoppe RT, Fuks Z, Bagshaw MA. The rationale for curative radiotherapy in mycosis fungoides. Int J Radiat Oncol Biol Phys 1977;2:843e851. Chowdhary M, Chhabra AM, Kharod S, Marwaha G. Total skin electron beam therapy in the treatment of mycosis fungoides: a review of conventional and low-dose regimens. Clin Lymphoma Myeloma Leuk 2016;16:662e671. https://doi.org/10. 1016/j.clml.2016.08.019. Gamble M, Tocci E, DeSimone JA. Low dose total skin electron beam radiation in cutaneous T-cell lymphoma: review. J Cancer Ther 2014;5:1372e1379. Ahmad OB, Boschi-Pinto C, Lopez AD, Murray CJL, Lozano R, Inoue M. Age standardization of rates: a new WHO standard. WHO; 2001. GPE Discussion Paper Series: No. 31. Freedman LS, Edwards BK, Ries LAG, Young JL, editors. Cancer incidence in four member countries (Cyprus, Egypt, Israel, and Jordan) of the Middle East Cancer Consortium (MECC) compared with US SEER. Bethesda, MD: National Cancer Institute; 2006. NIH Pub. No. 06e5873. Israel National Cancer Registry. Available at: http://www.iacr. com.fr/index.php?option¼com_comprofiler&task¼userProfile& user¼1207&Itemid¼498. [Accessed 20 March 2017]. Moraes FY, Carvalho Hde A, Hanna SA, Silva JL, Marta GN. Literature review of clinical results of total skin electron irradiation (TSEBT) of mycosis fungoides in adults. Rep Pract Oncol Radiother 2013;19:92e98. https://doi.org/10.1016/j.rpor. 2013.08.003. €kev€ Va a L, Pukkala E, Ranki A. Increased risk of secondary cancers in patients with primary cutaneous T cell lymphoma. J Invest Dermatol 2000;115:62e65. Pielop JA, Brownell I, Duvic M. Mycosis fungoides associated with malignant melanoma and dysplastic nevus syndrome. Int J Dermatol 2003;42:116e122.
Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006
M. Lutsyk et al. / Clinical Oncology xxx (2018) 1e7 [30] Olsen EA, Delzell E, Jegasothy BV. Second malignancies in cutaneous T cell lymphoma. J Am Acad Dermatol 1984;10: 197e204. [31] Tubiana M. Can we reduce the incidence of second primary malignancies occurring after radiotherapy? A critical review. Radiother Oncol 2009;91:4e15. https://doi.org/10.1016/j. radonc.2008.12.016. [32] Kirova YM, Piedbois Y, Haddad E, Levy E, Calitchi E, Marinello G, et al. Radiotherapy in the management of mycosis fungoides: indications, results, prognosis. Twenty years’ experience. Radiother Oncol 1999;51:147e151. [33] Kirova YM, Piedbois Y, Le Bourgeois JP. Radiotherapy in the management of cutaneous B-cell lymphoma. Our experience in 25 cases. Oncology 1999;52:15e18. [34] Huang KP, Weinstock MA, Clarke CA, McMillan A, Hoppe RT, Kim YH. Second lymphomas and other malignant neoplasms in patients with mycosis fungoides and Sezary syndrome: evidence from population-based and clinical cohorts. Arch Dermatol 2007;143:45e50. [35] Amichai B, Grunwald MH, Goldstein J, Finkelstein E, Halevy S. Small malignant melanoma in patients with mycosis fungoides. J Eur Acad Dermatol Venereol 1998;11:155e157. [36] Melanoma of skin, invasive tumors. Ministry of Health. Available at: https://www.health.gov.il/UnitsOffice/HD/ICDC/ ICR/CancerIncidence/Pages/Melanoma_Invasive.aspx. [Accessed 22 February 2017]. n J, Fenger[37] Lindahl LM, Kamstrup MR, Petersen PM, Wire Grøn M, Gniadecki R, et al. Total skin electron beam therapy for cutaneous T-cell lymphoma: a nationwide cohort study from Denmark. Acta Oncol 2011;50:1199e1205. https://doi. org/10.3109/0284186X.2011.585999. [38] Shore RE. Overview of radiation-induced skin cancer in humans. Int J Radiat Biol 1990;57:809e827.
7
[39] Licata AG, Wilson LD, Braverman IM, Feldman AM, Kacinski BM. Malignant melanoma and other second cutaneous malignancies in cutaneous T-cell lymphoma. Arch Dermatol 1995;131:432e435. [40] Navi D, Riaz N, Levin YS, Sullivan NC, Kim YH, Hoppe RT. The Stanford University experience with conventional-dose, total skin electron-beam therapy in the treatment of generalized patch or plaque (T2) and tumor (T3) mycosis fungoides. Arch Dermatol 2011;147:561e567. https://doi.org/10.1001/archdermatol.2011.98. [41] Braunstein S, Nakamura JL. Radiotherapy-induced malignancies: review of clinical features, pathobiology, and evolving approaches for mitigating risk. Front Oncol 2013;3: 73. https://doi.org/10.3389/fonc.2013.00073. [42] Evans AV, Scarisbrick JJ, Child FJ, Acland KM, Whittaker SJ, Russell-Jones R. Cutaneous malignant melanoma in association with mycosis fungoides. J Am Acad Dermatol 2004;50: 701e705. [43] Barcellos-Hoff MH. Integrative radiation carcinogenesis: interactions between cell and tissue responses to DNA damage. Semin Cancer Biol 2005;15:138e148. [44] Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW. Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991;51:6304e6311. [45] Radisky DC, Bissell MJ. Matrix metalloproteinase-induced genomic instability. Curr Opin Genet Dev 2006;16:45e50. [46] Reiss M, Barcellos-Hoff MH. Transforming growth factor-beta in breast cancer: a working hypothesis. Breast Cancer Res Treat 1997;45:81e95. [47] Purdy JA. Dose to normal tissues outside the radiation therapy patient’s treated volume: a review of different radiation therapy techniques. Health Phys 2008;95:666e676. https:// doi.org/10.1097/01.HP.0000326342.47348.06.
Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Original Article
Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study M. Lutsyk *, R. Ben-Yosef *y, R. Bergman yz, A. Kuten yx, G. Bar-Sela *y * Division
of Oncology, Rambam Health Care Campus, Haifa, Israel Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel z Department of Dermatology, Rambam Health Care Campus, Haifa, Israel x Department of Oncology, Italian Hospital, Haifa, Israel y
Received 13 February 2018; received in revised form 3 May 2018; accepted 22 May 2018
Abstract Aims: To determine the role of total skin electron irradiation (TSEI) as a cause of second malignancies in mycosis fungoides patients. Materials and methods: Mycosis fungoides patients referred to TSEI were followed in a longitudinal study. Other diagnosed malignancies were obtained after cross-matching with the Israel National Cancer Registry database. Results: Between 1974 and 2010, 197 patients were treated: 134 (68%) men, 63 (32%) women; mean age 58 17years. Topical/systemic treatment was given to 134 (68%) patients. TSEI was given to 104 (68.9%) patients. Seven (4.6%) received sub-TSEI and 40 (26.5%) received focal electron irradiation fields. Forty-six (23%) patients did not receive radiotherapy. The second primaries rate was 6.7 times higher in male mycosis fungoides patients and 13.1 times higher in female mycosis fungoides patients than in the general Israeli population. Malignant melanoma developed in eight patients after radiotherapy, in one patient without irradiation. The skin-related cancer rate after irradiation versus no irradiation was higher (P ¼ 0.018). Combination radiotherapy with psoralen þ ultraviolet A and/or nitrogen mustard yielded 11 cases of skin cancer versus no cases without irradiation. Conclusions: Mycosis fungoides patients have a high incidence of sequential malignancies. TSEI is associated with higher ‘skin-related cancer’ rates. Close longitudinal follow-up of mycosis fungoides patients is obligatory. Ó 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Key words: Longitudinal study; mycosis fungoides; sequential malignancies; skin electron beam radiotherapy; skin-related cancers
Introduction The extra-nodal T-cell lymphoma with predominant skin involvement, also known as mycosis fungoides, has low incidence with different world distribution rates [1e4]. The prognosis depends on the stage at presentation and varies from indolent, well-controlled with topical drugs to a very aggressive form with high mortality rates (Sezary syndrome) [5,6]. Medical treatment options are numerous and include skin-directed or systemic therapies and their combinations with different effectiveness for each method [7,8]. For decades, total skin electron beam irradiation (TSEI) has
Author for correspondence: G. Bar-Sela, Division of Oncology, Rambam Health Care Campus, POB 9602, Haifa 31096, Israel. Tel: þ972-4-7776409; Fax: þ972-4-7776427. E-mail address: [email protected] (G. Bar-Sela).
been considered as the most efficient approach to bring longstanding remission [9e12]. With long-lasting response to TSEI, however, there is an increasing risk of developing second primary malignancies. This phenomenon was described in several reports, illustrating that mycosis fungoides patients may suffer from other types of lymphoma or solid tumour, whether or not they were treated with radiotherapy [11,13e17] and speculation about the mycosis fungoides patient’s genotype as the underlying cause has been raised. The follow-up period for mycosis fungoides patients may continue for decades and, therefore, longitudinal prospective studies are extremely difficult, given the low incidence of the disease. This retrospective study describes and evaluates the rate of second malignancies in patients with mycosis fungoides referred to skin irradiation in one national centre dedicated to TSEI for 40 years. The purpose of the study was to determine the role of TSEI as
https://doi.org/10.1016/j.clon.2018.06.006 0936-6555/Ó 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006
2
M. Lutsyk et al. / Clinical Oncology xxx (2018) 1e7
the underlying cause of second malignancies in mycosis fungoides patients.
Patients and Methods Data Collection The study included retrospective data of all patients who were referred to Rambam Health Care Campus (RHCC) in Haifa, Israel for skin electron beam irradiation (SEI) from 1974 to 2010. Patients’ personal medical records were collected from hardcopy medical reports until 1990 and then from computerised records.
standardisation according to the Segi standard population [24]. The calculated age-standardised rate (ASR) (per 100 000 person-years) of malignancies within mycosis fungoides patients was compared with the ASR in the Israeli population updated to February 2016 (open web access). Differences in skin cancers between radiotherapy and non-radiotherapy patient groups were tested using the chisquared test. Data reported to the INCR on squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) were included only in the calculation for skin cancers and not for whole second malignancies due to possible unreported cases. Statistical analyses were carried out using SPSS 21.0 software for Windows.
Staging
Results In accordance with the last version of the TNM v7 staging system [18], all diseases were restaged based on description and images stored in the medical records and databases existing in RHCC. The study included all patients with stages mycosis fungoides IeIV. Epidemiological Data The final mycosis fungoides patient list was matched to the Israeli National Cancer Registry (INCR) data [19]. The INCR was asked for all malignancies registered in the study population. After strict authorisation procedures, the needed information was obtained and updated at the end of February 2016. Treatment before Radiotherapy Skin-directed cotherapeutic agents, narrow band ultraviolet B radiation (NBUVB), psoralen and ultraviolet A radiation (PUVA) and systemic interferon were used before referring the patients to the radiation unit in RHCC. Radiation Therapy Techniques and Doses The radiotherapy technique for TSEI used from 1970 until 1992 was the modified Christie Hospital translational technique described by Anacak et al. [20]. Since 1992, the six-dual Stanford technique has been used [21,22]. The delivered doses changed in accordance with published evidence from 36 Gy in 4 Gy one weekly fraction to 30 Gy in 1.2 Gy fractions for 5 days a week [23]. Several patients were treated with total body irradiation (TBI) of 1.25 Gy in 0.25 Gy fractions a week before and after TSEI [20]. The tumoural lesions required boosts in some cases. If skin lesions did not cover more than 10% of the body surface, subtotal or focal SEI only was used. Statistics The study protocol was created as for a retrospective cohort. Male and female mycosis fungoides patients were distributed to 16 age groups using the direct method of
Between 1974 and 2010, about 300 patients were referred to the RHCC Radiation Unit. Hardcopy and electronic data were kept for 197 patients: 134 (68%) men and 63 (32%) women. The rest of the medical records were not included due to logistical issues, with no selective criteria, which could have caused a bias. Among the patients were four children, ranging in age from 2 to 19 years, mean 10 7 years. The mean adult age was 58 17 years. The median observation time was 5.42 years and the maximum period of observation was 44 years (0.5e47 years). One hundred and thirty-four (68%) patients received topical or systemic treatment with one or several of the following agents: nitrogen mustard, NBUVB, PUVA, cotherapy (e.g. methotrexate) or immunotherapy (e.g. interferon). The whole group included 151 (77%) patients who were treated with radiotherapy (radiotherapy group) and 46 (23%) patients who were referred to radiotherapy, but did not receive the treatment for various reasons (nonradiotherapy group) (Table 1). Among the patients who received radiotherapy, 104 (68.8%) patients were treated with the TSEI approach and the mean delivered dose was 30.8 5.8 Gy. Seven patients were treated with subtotal SEI, with a mean dose of 31.46 6.18 Gy; 40 patients (26.5%) received focal electron irradiation field, with a mean dose 31.51 5.84 Gy. Four of Table 1 Patient characteristics Total number of patients Males (%) Females (%) Mean adult age, years (%) Mean child age, years (%) Treated with radiotherapy (%) Referred but not treated with radiotherapy (%) Pre-treated before radiotherapy (e.g. nitrogen mustard, NBUVB, PUVA, cotherapy or immunotherapy)
197 134 (68) 63 (32) 58.0 3 17.1 (98) 10 7 (2) 151 (77) 46 (23) 134 (68)
NBUVB, narrow band ultraviolet radiation; PUVA, psoralen þ ultraviolet A treatment.
Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006
M. Lutsyk et al. / Clinical Oncology xxx (2018) 1e7
151 patients in the radiotherapy group were treated with TBI at a dose of 1.25 Gy. Fifteen patients with mycosis fungoides relapse after TSEI were treated with radiotherapy: three patients with another course of TSEI (2%, mean dose 20 4.5 Gy), one patient with subtotal SEI (16 Gy), and 11 patients with focal electron beam irradiation (7.2%, mean dose 17 7.4 Gy). Of the nine (6%) patients who relapsed after non-TSEI, four were treated with TSEI (2.7%, mean dose 30 6.3 Gy) and five patients received non-TSEI (3.3%, mean dose 29.3 5.8 Gy). Demographic data on the incidence of cancer in the Israeli population published in 2016 reported incidences of: Jewish males 385.77, Jewish females 462.63, Arabic males 152.17 and Arabic females 161.53 cases per 100 000 persons. INCR data do not include incidences of BCC and SCC of the skin after 2007 [25,26]. Using the data and crude cancer incidence, the incidence without BCC and SCC among mycosis fungoides patients was compared with the cancer incidence of the whole population. After cross-matching the RHCC data with INCR data, 82/197 (41.6%) patients had other malignancies. Among the 151 patients in the radiotherapy group, 64 (42.4%) had additional oncological and/or haematological malignancies, whereas 18 cases of 46 patients (39.1%) in the non-radiotherapy group were registered (Table 2). Table 2 shows the profile of malignancies that appeared in both groups. The most frequent solid tumours in the radiotherapy group were non-melanoma skin malignancies, malignant melanoma, gastrointestinal and genitourinary tumours and Kaposi’s sarcoma. Lymphomas (Hodgkin and non-Hodgkin types) were registered as the main haematological malignancies. Among patients in the nonradiotherapy group, the most frequent solid tumours were genitourinary tumours, breast cancer and non-melanoma skin malignancies. Non-Hodgkin’s lymphomas were the most frequent haematological malignancies in this group as well. There was no statistical significance between the
3
groups in the incidence of total solid and haematological malignancies (P ¼ 0.86). In most of the patients, second malignancies appeared after the diagnosis of mycosis fungoides. In the radiotherapy group of 151 patients, 42 had second primaries. Of these, 13 had third primaries; fourth primaries were found in two of those 13. Among the 46 patients in the nonradiotherapy group, 12 had second primaries, four of whom had third primaries; one of those four had a fourth primary. However, in 22 of the 151 patients treated with radiotherapy, mycosis fungoides was diagnosed as a second primary; in three of those 22, mycosis fungoides was the third malignancy in chronological order. Also, in six of the 46 patients who were not treated with radiotherapy, mycosis fungoides was the second malignancy; in one of those six, mycosis fungoides was the third malignancy. In total, 64 patients in the radiotherapy group developed 82 other malignancies, whereas 18 patients in the nonradiotherapy group developed 24 malignant diseases (Table 3). The ASR of sequential malignancies for all age groups was calculated. The incidence of second primaries in male mycosis fungoides patients was 6.7 times higher than in the general male Israeli population; the incidence of second primaries in female mycosis fungoides patients was 13.1 times higher than in the general female Israeli population. In male mycosis fungoides patients, the rate was increased after 40 years of age, with peaks at ages 50, 60 and 75 years. In female mycosis fungoides patients, the increased rate was observed in four peaks at ages 25, 40, 55 and 75 years. The rates in men and women were similar and higher than in the general Israeli population after 60e65 years of age (Figure 1). The curves of male and female malignancy rates among mycosis fungoides patients climb after age 40e49 years, whereas the Segi standardised world population curve goes down, crossing at the same ages.
Table 2 Type of sequential malignancies among mycosis fungoides patients Site or type of malignancy
Radiotherapy patients (total n ¼ 151)
Non-radiotherapy patients (total n ¼ 46)
Lymphoma (non-mycosis fungoides type) Merkel’s cell carcinoma Gastrointestinal malignancies Genitourinary malignancies Kaposi’s sarcoma Breast malignancies Melanoma Gynaecological malignancies Thyroid malignancies Brain malignancies Endocrine malignancies Leukaemia Lung malignancies Parotid malignancies Sarcoma Unknown primary carcinoma
19 (12.6%) 1 (0.7%) 7 (4.6%) 6 (4.0%) 5 (3.3%) 3 (2.0%) 8 (5.3%) 2 (1.3%) 2 (1.3%) 2 (1.3%) 2 (1.3%) 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)
6 0 1 7 0 3 1 1 1 0 0 1 1 0 0 0
(13%) (2.2%) (15.2%) (6.5%) (2.2%) (2.2%) (2.2%)
(2.2%) (2.2%)
Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006
4
M. Lutsyk et al. / Clinical Oncology xxx (2018) 1e7
Table 3 Appearance of malignancies among mycosis fungoides patients
Radiotherapy group Non-radiotherapy group Total
Patients (n)
Mycosis fungoides patients, without second malignancies n (%)
Mycosis fungoides patients with other malignancies n (%)
Total number of other cancer diagnoses
151 46 197
87 (57.6) 28 (60.8) 115 (58.4)
64 (42.4) 18 (39.1) 82 (41.6)
82 24 106
Four patients were treated with TBI. In three patients, TBI preceded TSEI treatment. All three had a second malignancy and two had a third primary. No additional malignancy was registered in the patient who had only TBI. No sequential malignancies were found in the subgroup of four children. Skin Cancers In the radiotherapy group, eight patients had a malignant melanoma. One had acral lentiginous, two had superficial spreading, three had in situ melanomas and two had invasive melanomas. All patients received TSEI. In the nonradiotherapy group, only one patient had invasive melanoma. In the radiotherapy group, one patient with malignant melanoma was also treated with TBI. Kaposi’s sarcoma was diagnosed in five patients from the radiotherapy group. In the radiotherapy group, 33 cases of all types of invasive and non-invasive skin cancer (malignant melanoma,
Merkel’s cell carcinoma, Kaposi’s sarcoma, SCC, BCC) were diagnosed, compared with only three cases in the nonradiotherapy group. The incidence of skin-related cancers due to SEI was statistically higher in patients in the radiotherapy group (P ¼ 0.018). As previous treatments with PUVA and/or nitrogen mustard have cancerogenic potential and may be considered as a risk factor for skin cancer, their use in the study population is shown in Table 4. In the radiotherapy group, the combination of these two agents and electron beam irradiation of skin added somewhere in the course of treatment resulted in two (5%) skin cancer cases among 39 (26%) patients who received PUVA treatment, eight (21%) skin cancer cases among 16 patients treated with nitrogen mustard and one (3%) case of skin cancer of 13 patients after combination PUVA and nitrogen mustard. In the non-radiotherapy group, no skin cancer was registered, although 15 patients received PUVA, five patients received nitrogen mustard and two patients both.
Fig 1. Secondary malignancies in mycosis fungoides (MF) patients and rate of malignancies in the Israeli population (age-standardised ratio calculated for both). Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006
M. Lutsyk et al. / Clinical Oncology xxx (2018) 1e7
5
Table 4 Skin cancer after skin-directed agents in combination with radiotherapy Skin-directed agents
Radiotherapy group, Total n ¼ 151
No radiotherapy group, Total n ¼ 46
Patients n (%)
Skin cancer cases (%)
Patients n (%)
Skin cancer cases
NBUVB, PUVA Nitrogen mustard NBUVB, PUVA, nitrogen mustard
39 (26%) 16 (11%) 13 (9%)
2 (5%) 8 (21%) 1 (3%)
15 (33%) 5 (11%) 2 (4%)
0 0 0
NBUVB, narrow band ultraviolet radiation; PUVA, psoralen þ ultraviolet A treatment.
Discussion As the only national dedicated centre for SEI applied to mycosis fungoides patients in Israel, we have followed our patients for 42 years. To the best of our knowledge, the current report has the longest follow-up period ever reported in the literature. Using the INCR service, we have observed longitudinally and, in some cases, for a lifetime, the development of sequential tumours in persons suffering from mycosis fungoides [14]. Given the absence of differences in the incidence of sequential tumours between radiotherapy and non-radiotherapy groups, we believe that TSEI is not the only factor in the development of second malignancies [27e29] A new study with more patients from many centres, combined with a web-based database for a long-term observation period, may provide wider answers to this question. The high incidence of solid cancers and/or haematological malignancies may be explained by an intrinsic defect in the immune system response to the appearance of cancer cells within solid tissue or blood. It was reported that mycosis fungoides patients have other types of lymphoma or solid tumour [14,30,31]. The structure of second tumour morbidity presents a wide spectrum of malignancies, pointing at multiple defects explaining the sequential tumour appearing in both irradiated and unirradiated patients. The most frequent malignancy among mycosis fungoides patients is haematological, as shown in several studies [17,32,33]. The incidence of solid tumours was reviewed in studies from several centres and revealed a higher age-specific standardised population ratio (ASR) among mycosis fungoides patients who received radiotherapy or not [14,28,27,34]. The current study confirms those results. Consideration of causes and triggers launching an oncogenesis in different tissues in mycosis fungoides patients is beyond the scope of the current discussion. However, some notes are worth making. Topical application of nitrogen mustard in some patients may cause the development of malignant melanoma [35]. Eight cases of malignant melanoma were found in the radiotherapy group and in one case in the non-radiotherapy group. All nine cases of melanoma in mycosis fungoides presented a higher incidence than in the Israeli population [36]. The number of patients with melanoma was higher in the group following TSEI. PUVA treatment was reviewed in the late 1980s. The benefits and risks of its combination with other skin-
directed topical agents were studied in several large trials (e.g. a nationwide cohort study from Denmark) [37]. Several studies concluded that the combination of ultraviolet, psoralen and ionising radiation may increase ‘the expression of skin cancer’ [11,38e40]. In the current study, we considered all ‘skin-related cancers’ as one group. Although the skin cancers differed in their prognosis, they all represented a significant illness reported to the Israeli Cancer Registry [25]. Superficial BCC and SCC of the skin are not reported to the Registry [26]. Those reported and included in the current analysis represent more significant tumours that cause patient referral to oncology treatment. Although data on superficial BCC and SCC are missing, the conclusion of elevated skin-related cancers after skin irradiation can be defined based on the current data and a ‘causeeeffect’ correlation can be established. The risk of developing a second primary after radiation exposure is elevated independent of the type of radiotherapy modality [41]. Specific data on the influence of electron beam skin irradiation on second primary development are scarce and do not provide the underlying mechanism to explain the oncogenesis [42], although the ‘bystander effect’ on deep layers of skin may partly explain it. The influence of irradiation on the microenvironment of unirradiated skin cells results in abnormal extracellular signalling causing diminished abnormal cell suppression [43]. The process involves many factors, such as disturbances in cell adhesion, tumour suppressor p53 and response to radiation stress of transforming growth factor b1 (TGFb1) functioning, and stroma cell changes that eventually contribute to neoplastic progression [43e46]. Sparing of normal tissue volume is a primary concept of intensity-modulated radiation therapy [47]. However, in the case of mycosis fungoides, the skin is the main organ ‘targeted’ by disease and, therefore, TSEI is a whole organ irradiation that narrows the therapeutic window due to giving of a biologically effective dose escalation without minimising normal skin toxicity [23]. One toxicity type is a second malignancy development [22], as reported in the current study.
Conclusions Mycosis fungoides patients have a high incidence of sequential malignancies in almost every system of the human body, not related to skin irradiation. Nevertheless,
Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006
6
M. Lutsyk et al. / Clinical Oncology xxx (2018) 1e7
electron skin irradiation is associated with a higher incidence of ‘skin-related cancers’ among these patients. This observation should be included in the ‘patient informed consent’ before skin irradiation. Due to the retrospective data collection, some interesting points, such as areas of re-irradiation and sites of SCC or BCC appearance, exact surface area of focal irradiation or detailed on-treatment skin toxicity assessment, cannot be clarified.
Acknowledgement Thank you to the Israel National Cancer Registry for linking our patient cohort to the registry database for the purpose of identifying second primary malignancies.
[13]
[14]
[15] [16]
[17]
References [1] Weinstock MA, Gardstein B. Twenty-year trends in the reported incidence of mycosis fungoides and associated mortality. Am J Public Health 1999;89:1240e1244. [2] Beltran B, Morales D, Quinones P, Salas R, Carrasco-Yalan AA. Distribution and pathology characteristics of non Hodgkin lymphoma in Peru: a study of 1014 cases using WHO classification of lymphoid neoplasm. Blood ASH Annu Meet Abstr 2007;110:4419. [3] Sukpanichnant S, Sonakul D, Piankijagum A, Wanachiwanawin W, Veerakul G, Mahasandana C, et al. Malignant lymphoma in Thailand: changes in the frequency of malignant lymphoma determined from a histopathologic and immunophenotypic analysis of 425 cases at Siriraj Hospital. Cancer 1998;83: 1197e1204. [4] Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973e2002. Arch Dermatol 2007;143:854e859. [5] Weinstock MA, Horm JW. Population-based estimate of survival and determinants of prognosis in patients with mycosis fungoides. Cancer 1988;62:1658e1661. [6] Kim YH, Bishop K, Varghese A, Hoppe RT. Prognostic factors in zary syndrome. erythrodermic mycosis fungoides and the Se Arch Dermatol 1995;131:1003e1008. [7] Kaye FJ, Bunn Jr PA, Steinberg SM, Stocker JL, Ihde DC, Fischmann AB, et al. A randomized trial comparing combination electron-beam radiation and cotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 1989;321:1784e1790. [8] Bagherani N, Smoller BR. An overview of cutaneous T cell lymphomas. F1000Res 2016;5. https://doi.org/10.12688/ f1000research.8829.1. [9] Le Bourgeois JP, Haddad E, Marinello G, Marin L, Mazeron JJ, Ganem G. The indications for total cutaneous electron beam radiation therapy of mycosis fungoides. Int J Radiat Oncol Biol Phys 1987;13:189e193. [10] Tadros AA, Tepperman BS, Hryniuk WM, Peters VG, Rosenthal D, Roberts JT, et al. Total skin electron irradiation for mycosis fungoides: failure analysis and prognostic factors. Int J Radiat Oncol Biol Phys 1983;9:1279e1287. [11] Stein ME, Anacak Y, Zaidan J, Drumea K, Gez E, Bar-Deroma R, et al. Second primary tumors in mycosis fungoides patients: experience at the Northern Israel Oncology Center (1979e2002). J Buon 2006;11:175e180. [12] Chinn DM, Chow S, Kim YH, Hoppe RT. Total skin electron beam therapy with or without adjuvant topical nitrogen
[18] [19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys 1999;43: 951e958. Huang KP, Weinstock MA, Clarke CA, McMillan A, Hoppe RT, Kim YH. Second lymphomas and other malignant neoplasms in patients with mycosis fungoides and Sezary syndrome: evidence from population-based and clinical cohorts. Arch Dermatol 2007;143:45e50. Kantor AF, Curtis RE, Vonderheid EC, van Scott EJ, Fraumeni Jr JF. Risk of second malignancy after cutaneous Tcell lymphoma. Cancer 1989;63:1612e1615. Barzilai A, Trau H, David M, et al. Mycosis fungoides associated with B-cell malignancies. Br J Dermatol 2006;155:379e386. Hallermann C, Kaune KM, Tiemann M, Kunze E, Griesinger F, Mitteldorf C, et al. High frequency of primary cutaneous lymphomas associated with lymphoproliferative disorders of different lineage. Ann Atol 2007;86:509e515. Hodak E, Lessin S, Friedland R, Freud T, David M, Pavlovsky L, et al. New insights into associated co-morbidities in patients with cutaneous T-cell lymphoma (mycosis fungoides). Acta Derm Venereol 2013;93:451e455. https://doi.org/10.2340/ 00015555-1496. AJCC cancer staging atlas. New York: Springer; 2012. https:// doi.org/10.1007/978-1-4614-2080-4. National Cancer Registry, Ministry of Health. Available at: https:// www.health.gov.il/English/MinistryUnits/HealthDivision/Icdc/ Icr/Pages/default.aspx. [Accessed 21 February 2017]. Anacak Y, Arican Z, Drumea K, Rosenblatt E, Tamir A, Chetver L, et al. Total skin electron irradiation in mycosis fungoides: comparison between a modified Christie Hospital translational technique and the Stanford technique. Leuk Lymphoma 2002;43:2093e2097. Hoppe RT, Fuks Z, Bagshaw MA. The rationale for curative radiotherapy in mycosis fungoides. Int J Radiat Oncol Biol Phys 1977;2:843e851. Chowdhary M, Chhabra AM, Kharod S, Marwaha G. Total skin electron beam therapy in the treatment of mycosis fungoides: a review of conventional and low-dose regimens. Clin Lymphoma Myeloma Leuk 2016;16:662e671. https://doi.org/10. 1016/j.clml.2016.08.019. Gamble M, Tocci E, DeSimone JA. Low dose total skin electron beam radiation in cutaneous T-cell lymphoma: review. J Cancer Ther 2014;5:1372e1379. Ahmad OB, Boschi-Pinto C, Lopez AD, Murray CJL, Lozano R, Inoue M. Age standardization of rates: a new WHO standard. WHO; 2001. GPE Discussion Paper Series: No. 31. Freedman LS, Edwards BK, Ries LAG, Young JL, editors. Cancer incidence in four member countries (Cyprus, Egypt, Israel, and Jordan) of the Middle East Cancer Consortium (MECC) compared with US SEER. Bethesda, MD: National Cancer Institute; 2006. NIH Pub. No. 06e5873. Israel National Cancer Registry. Available at: http://www.iacr. com.fr/index.php?option¼com_comprofiler&task¼userProfile& user¼1207&Itemid¼498. [Accessed 20 March 2017]. Moraes FY, Carvalho Hde A, Hanna SA, Silva JL, Marta GN. Literature review of clinical results of total skin electron irradiation (TSEBT) of mycosis fungoides in adults. Rep Pract Oncol Radiother 2013;19:92e98. https://doi.org/10.1016/j.rpor. 2013.08.003. €kev€ Va a L, Pukkala E, Ranki A. Increased risk of secondary cancers in patients with primary cutaneous T cell lymphoma. J Invest Dermatol 2000;115:62e65. Pielop JA, Brownell I, Duvic M. Mycosis fungoides associated with malignant melanoma and dysplastic nevus syndrome. Int J Dermatol 2003;42:116e122.
Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006
M. Lutsyk et al. / Clinical Oncology xxx (2018) 1e7 [30] Olsen EA, Delzell E, Jegasothy BV. Second malignancies in cutaneous T cell lymphoma. J Am Acad Dermatol 1984;10: 197e204. [31] Tubiana M. Can we reduce the incidence of second primary malignancies occurring after radiotherapy? A critical review. Radiother Oncol 2009;91:4e15. https://doi.org/10.1016/j. radonc.2008.12.016. [32] Kirova YM, Piedbois Y, Haddad E, Levy E, Calitchi E, Marinello G, et al. Radiotherapy in the management of mycosis fungoides: indications, results, prognosis. Twenty years’ experience. Radiother Oncol 1999;51:147e151. [33] Kirova YM, Piedbois Y, Le Bourgeois JP. Radiotherapy in the management of cutaneous B-cell lymphoma. Our experience in 25 cases. Oncology 1999;52:15e18. [34] Huang KP, Weinstock MA, Clarke CA, McMillan A, Hoppe RT, Kim YH. Second lymphomas and other malignant neoplasms in patients with mycosis fungoides and Sezary syndrome: evidence from population-based and clinical cohorts. Arch Dermatol 2007;143:45e50. [35] Amichai B, Grunwald MH, Goldstein J, Finkelstein E, Halevy S. Small malignant melanoma in patients with mycosis fungoides. J Eur Acad Dermatol Venereol 1998;11:155e157. [36] Melanoma of skin, invasive tumors. Ministry of Health. Available at: https://www.health.gov.il/UnitsOffice/HD/ICDC/ ICR/CancerIncidence/Pages/Melanoma_Invasive.aspx. [Accessed 22 February 2017]. n J, Fenger[37] Lindahl LM, Kamstrup MR, Petersen PM, Wire Grøn M, Gniadecki R, et al. Total skin electron beam therapy for cutaneous T-cell lymphoma: a nationwide cohort study from Denmark. Acta Oncol 2011;50:1199e1205. https://doi. org/10.3109/0284186X.2011.585999. [38] Shore RE. Overview of radiation-induced skin cancer in humans. Int J Radiat Biol 1990;57:809e827.
7
[39] Licata AG, Wilson LD, Braverman IM, Feldman AM, Kacinski BM. Malignant melanoma and other second cutaneous malignancies in cutaneous T-cell lymphoma. Arch Dermatol 1995;131:432e435. [40] Navi D, Riaz N, Levin YS, Sullivan NC, Kim YH, Hoppe RT. The Stanford University experience with conventional-dose, total skin electron-beam therapy in the treatment of generalized patch or plaque (T2) and tumor (T3) mycosis fungoides. Arch Dermatol 2011;147:561e567. https://doi.org/10.1001/archdermatol.2011.98. [41] Braunstein S, Nakamura JL. Radiotherapy-induced malignancies: review of clinical features, pathobiology, and evolving approaches for mitigating risk. Front Oncol 2013;3: 73. https://doi.org/10.3389/fonc.2013.00073. [42] Evans AV, Scarisbrick JJ, Child FJ, Acland KM, Whittaker SJ, Russell-Jones R. Cutaneous malignant melanoma in association with mycosis fungoides. J Am Acad Dermatol 2004;50: 701e705. [43] Barcellos-Hoff MH. Integrative radiation carcinogenesis: interactions between cell and tissue responses to DNA damage. Semin Cancer Biol 2005;15:138e148. [44] Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW. Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991;51:6304e6311. [45] Radisky DC, Bissell MJ. Matrix metalloproteinase-induced genomic instability. Curr Opin Genet Dev 2006;16:45e50. [46] Reiss M, Barcellos-Hoff MH. Transforming growth factor-beta in breast cancer: a working hypothesis. Breast Cancer Res Treat 1997;45:81e95. [47] Purdy JA. Dose to normal tissues outside the radiation therapy patient’s treated volume: a review of different radiation therapy techniques. Health Phys 2008;95:666e676. https:// doi.org/10.1097/01.HP.0000326342.47348.06.
Please cite this article in press as: Lutsyk M, et al., Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study, Clinical Oncology (2018), https://doi.org/10.1016/j.clon.2018.06.006