Desiree Wiegleb Edström and Mari-Anne Hedblad
Department of Dermatology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail: desiree.wiegleb-edstrom@karolinska.se
Accepted October 22, 2007.
Desiree Wiegleb Edström and Mari-Anne Hedblad
Department of Dermatology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail: desiree.wiegleb-edstrom@karolinska.se
Accepted October 22, 2007.
Sir,
Mycosis fungoides (MF) is a primary, cutaneous, T-cell lymphoma characterized by slow progress over years or decades, developing from patches to more infiltrated plaques and sometimes to tumours (1). The incidence per general population of cutaneous lymphomas is estimated as 0.4–1 in 100,000 per year (2, 3).
Patients with patch/plaque-stage MF and less than 10% of the skin involved have survival rates similar to that of an age-, sex-, and race-matched population (4). Survival rates decrease with the area of skin involvement and with more infiltrated lesions such as tumour-stage MF (4, 5).
There is no curative treatment for MF. Topical therapy, such as corticosteroids, nitrogen mustard or carmustine, photochomotherapy (psoralen + ultraviolet A; PUVA), radiotherapy, immunotherapy, chemotherapy, monoclonal antibody therapy and novel retinoids, can be used (3). Photodynamic therapy (PDT) has been used in several cases, but without long-term follow-up (6–15; Table I).
Table I. Summary of published studies using photodynamic therapy (PDT) for mycosis fungoides
| Reference | No. of lesions | Stage | No. of PDT | Lesions in remission (%) | Clinical follow-up | Histological follow-up |
| Svanberg et al. (6) | 4 | Not reported | 1–2 | 2 (50) | 6–14 months | Not reported |
| Wolf et al. (7) | 3 | Plaque | 4–5 | 3 (100) | 3–6 months | 6 weeks |
| Ammann (8) | 1 | Plaque | 1 | None (0) | 24 days | 24 days |
| Eich et al. (9) | 2 | Tumour | 12 | 2 (100) | 24 months | 2 weeks |
| Orenstein et al. (10) | 1 5 | Patch Tumour | 1 1 | 1 (100) 5 (100) | 27 months 24 months | 3 months 3 months |
| Markham (11) | 1 | Tumour | 5 | 1 (100) | 12 months | Was done |
| Leman et al. (12) | 2 | Plaque | 4 | 2 (100) | 12 months | 6 weeks |
| Coors et al. (14) | 1 3 | Plaque Plaque | 2 6–7 | 1 (100) 3 (100) | 18 months 14 months | Not done |
| Zane et al. (15) | 5 | Patch | 1–9 | 4 (80) | 12–34 months | End of treatment |
We performed a long-term (6–9 years) follow-up of 10 patients with plaque-stage MF treated with PDT.
MATERIALS AND METHODS
Ten patients with MF (6 men and 4 women, mean age 67 years, age range 58–81 years) participated in the study and received PDT treatment during 1995 to 1999. In 2 patients, 2 lesions were treated. Ten lesions were at the plaque stage of MF and 2 were tumour stage MF. The diagnosis was confirmed with routine histopathology and immunophenotyping. Only one patient (no. 3; Table II) had enlarged lymph nodes on the neck (tumour, node, metastasis (TNM) classification T1, N1, M0). The other patients had no signs of internal involvement. More patient characteristics are shown in Table II and further information is given in the previous publication (13).
Table II. Characteristics of patients, mycosis fungoides (MF) lesions, photodynamic therapy (PDT) and clinical results
| Patient number/gender | Previous treatment | MF lesion | Location of lesion | Fluence (J/cm2) | No. of PDTs | First follow-up | After first follow-up | Second follow-up |
| 1/M | PUVA PUVA | Plaque Plaque | Thigh Hip | 90 50+30 | 2 2 | Healed Regression | PUVA, UVA1, Radiotherapy, methotrexate Interferon | Healed |
| 2/M | Local steroids | Plaque | Hip | 180 | 2 | Healed | Developed tumour MF in the face | Died 2003 |
| 3/M | PUVA PUVA | Tumour Plaque | Trunk Back | 180 180 | 3 3 | No response Healed | Developed tumour MF on the leg | Died 1998 |
| 4/F | PUVA | Plaque | Thigh | 90 | 2 | Healed | Developed tumour MF on lower leg and in face | Died 2001 |
| 5/M | None | Plaque | Gluteal | 50+60 | 2 | Healed | No treatment | Healed |
| 6/M | None | Plaque | Gluteal | 90 | 8 | No response | ||
| 7/M | Radiotherapy PUVA | Plaque | Arm | 90 | 11 | Healed | No treatment | Healed |
| 8/F | PUVA | Tumour | Abdomen | 100 | 3 | No response | ||
| 9/F | PUVA | Plaque | Trunk | 90 | 3 | Healed | No treatment | Healed |
| 10/F | PUVA | Plaque | Thigh | 90+50 | 2 | Regression | ||
| PUVA: psoralen plus ultraviolet A. | ||||||||
Twenty percent 5-aminolevulinic acid (ALA) (Phorpyrin Products, Utah, USA), dissolved in an oil-water emulsion, was applied topically to the lesion and to adjacent skin under an occluding and light-shielding dressing for 5–6 h. The red fluorescence of porphyrins was visualized with Wood’s light before treatment. The ALA-treated areas were then exposed to incoherent light using a Waldmann PDT 1200 (Waldmann Medical Division, Villingen-Schwenningen, Germany) and emitting light at a wavelength of 600–730 nm with a maximum around 630 nm. The patients were treated with intervals of 1–2 weeks, 2–11 times (median 2.5 times) (Table II). The first follow-up, at 4–21 months after the last PDT, showed clinically complete clearance in 7 of 9 plaque lesions (13). Biopsies were taken after treatment in 9 patients. Histological evaluation and CD3 staining confirmed a significant regression of the infiltrate in all cases studied. In clinically responding lesions, the biopsies showed no remaining atypical infiltrates (13). The 2 tumour-stage MFs did not respond to treatment.
The follow-up reported in this study was performed during 2004 to 2005. Patients were examined on the area previously treated with PDT and a 4-mm punch biopsy was taken. The biopsy was formalin-fixed and embedded in paraffin. For histological evaluation, routine haematoxylin-eosin-stained sections were used.
The study was approved by the local ethics committee.
RESULTS
This second follow-up was performed between 5 years and 11 months and 8 years and 10 months after the last PDT, with a median interval of 7.25 years.
Three of the 7 patients with plaque MF who showed clinical and histological clearance in the first follow-up had died before the second follow-up. All 3 patients had developed tumour-stage MF with metastasis, but not in the areas previously treated with PDT, according to clinical information collected from the hospital records (Table II).
The other 4 patients (no. 1, 5, 7 and 9) had no relapse of MF in the area treated with PDT. Three of the healed patients had received no further treatment for MF (no. 5, 7 and 9). The fourth patient had been treated with methotrexate, retinoids, interferon, PUVA, UVA1 (long-wave-ultraviolet-A radiation) and local radiotherapy to the face, buttock, thigh and neck.
All 4 patients fulfilled the criteria for cutaneous lymphoma of MF type in routine histological examination prior to PDT. The biopsies taken at the second follow-up showed loss of lymphocytic infiltrate in all 4 patients.
DISCUSSION
Svanberg et al. (6) showed already in 1994 a clinically complete response in 2 of 4 lesions of T-cell lymphomas treated once or twice with PDT (see Table I).
Eich et al. (9) treated a patient with tumour-cutaneous T-cell lymphoma with 8 sessions of PDT. Biopsy showed remission at 1.5 mm depth, but an infiltrate of lymphocytes remained deeper in the skin. The second patient with a tumour MF was treated with 12 PDT sessions. Biopsy taken 2 weeks after completed PDT showed no infiltrate of lymphocytes. The patient was followed up at 24 months with no clinical relapse, but was also treated with PUVA and interferon during that time.
Our experience is that PDT is not efficient on tumour MF. This might be due to lack of penetration of the ALA and/or the light. Zane et al. (15) used methylaminolevulinate (MAL) for treating patch stage MF. MAL has a higher penetration because of its increased lipophilic properties.
Our study started in 1995 when little was known about the optimal fluence. Initially, a fluence of 180 J/cm2 was given, but this had to be halved because of troublesome pain. However, even patients treated with lower fluences healed, suggesting that higher fluence should be avoided because of more pain.
We noticed that the treatment of larger plaque lesions with a diameter of 7.5 cm or more was less successful (see Table II). One large lesion healed, but had to be treated 11 times (no. 7). Two patients with larger MF plaques lesions (nos. 1 and 10) showed a regression, but did not heal completely. Patient no. 10 discontinued PDT because of pain. That treatment of larger skin tumours results in more pain is an old observation (16). This might be an effect of more malignant cells accumulating photosensitizing protoporphyrin in the target cells.
Prior to this study, the longest clinical follow-up (1–3 years) is reported by Zane et al. (15), but they had no histological follow-up. We had 4 patients with clinical and histological MF in remission at the area treated with PDT. Three of these had not received any other treatment. The fourth patient had had several other treatments and is therefore difficult to evaluate, but no new lesions developed in the area treated with PDT. Three patients who were healed at the PDT location died 2–7 years later. It is interesting to note that none of these developed a tumour MF in the region of PDT.
ACKNOWLEDGEMENT
This work was supported by funds from the Welander-Finsen Foundation.
REFERENCES
1. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768–3785.
2. Weinstock MA. Epidemiology of mycosis fungoides. Sem Dermatol 1994; 13: 154–159.
3. Whittaker SJ, Marsden JR, Spittle M, Russell Jones R. Joint British Association of Dermatologists and UK Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell lymphomas. Br J Dermatol 2003; 149: 1095–1107.
4. Zackheim HS, Amin S, Kashani-Sabet M, McMillan A. Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol 1999; 40: 418–425.
5. Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Long-term outcome of 525 patients with mycosis fungoides and Sézary syndrome. Arch Dermatol 2003; 139: 857–866.
6. Svanberg K, Andersson T, Killander D, Wang I, Stenram U, Andersson-Engels S, et al. Photodynamic therapy of non-melanoma malignant tumours of the skin using topical δ–aminolevulinic acid sensitisation and laser irradiation. Br J Dermatol 1994; 130: 743–751.
7. Wolf P, Fink-Puches R, Cerroni L, Kerl H. Photodynamic therapy for mycosis fungoides after topical photosensitization with 5-aminolevulinic acid. J Am Acad Dermatol 1994; 31: 678–680.
8. Amman, R. Photodynamic therapy for mycosis fungoides after topical photosensitization with 5-aminolevulinic acid. J Am Acad Dermatol 1995; 32: 541.
9. Eich D, Eich HT, Otte TH, Ghilescu H-G, Stadler R. Photodynamishce Therapie kuntaner T-Zell-Lymphome in besonderer Lokalisation. Hautarzt 1999; 50: 109–114.
10. Oreinstein A, Haik J, Tamir J, Winkler E, Trau H, Malik Z, et al. Dermatol Surg 2000; 26: 765–769.
11. Markham T. Topical 5-aminolaevulinic acid photodynamic therapy for tumour-stage mycosis fungoides. Br J Dermatol 2001; 144: 1262–1295.
12. Leman JA, Dick DC, Morton CA. Topical 5-ALA photodynamic therapy for the treatment of cutaneous T-cell lymphoma. Clin Exp Dermatol 2002; 27: 516–518.
13. Edstrom DW, Porwit A, Ros A-M. Photodynamic therapy with topical 5-aminolevulinic acid for mycosis fungoides: clinical and histological response. Acta Derm Venereol 2001; 81: 184–188.
14. Coors EA, von den Driesch P. Topical photodynamic therapy for patients with therapy-resistant lesions of cutaneous T-cell lymphoma. J Am Acad Dermatol 2004; 50: 363–367.
15. Zane C, Venturini M, Sala R, Calzavara-Pinto P. Photodynamic therapy with methylaminolevulinate as a valuable treatment option for unilesional cutaneous T-cll lymphoma. Photodermatol Photoimmunol Photomed 2006; 22: 254–258.
16. Grapengiesser S, Gudmundsson F, Larkö O, Ericson M, Rosén, Wennberg A-M. Pain caused by photodynamic therapy of skin cancer. Clin Exp Dermatol 2002; 27: 493–497.
