Aust. J. Derm. (1980) 21, 100

THE TREATMENT OF MYCOSIS FUNGOIDES WITH PUVA*

H. RoTSTEiN,t J- M. BuTLER,t D. B. CZARNECK!,^ T . J. O'BuiBNt and M. T. GBORGE**

Twenty patients with mycosis fungoides were treated wifh photochemolherapyusing oral psoralens and long wave ultraviolet light {PUVA) over a two-year period.PUVA was effective in producing a diminution of cutaneous deposits of mycosisfungoides with each clinical pattern of presentation. In most patients complete clearingcould not be achieved, and in those considered free of disease, sustained total clearingoff PUVA could not be maintained. Lack of response to the effect of PUVA ifreinstituted for recurrence of disease did not occur.

The palliative use of PUVA for the treatment of mycosis fungoides is recom-mended.

INTRODUCTION

In 1974 Winkelman suggested photo-chemotherapy with oral psoralens and long waveuitravioiet light (PUVA) as a Ucnunan formycosis fungoides (M.F.).' Subsequent reportshave confirmed that the cutaneous manifesta-tions of M.F. resolve if treated withPUVA.--'-*'^ Because it has been claimed tlialtreatment of early M.F. with topical nitrogenmustard." or whole body electron beam tlierapy'can be curative, we attempted to assess the roleof PUVA as a curative treatment in patientswith cariy M.F.

Ml:TIIODS

Patients: Twenty patients with M.F. in vary-ing stages were treated during a two-year period(Table 1). Most of ihe paiicnis were referred forPUVA treatment with the diagnosis alreadymade.

Diagnosis: The clinical diagnosis was con-firmed on the basis of characteristic lightmicroscopic appearances and electronmicroscopy dcmonsirating many ce!)s with ihetypical deeply cleft nuclei.

Prescnicd M ihc Animal Mccling of The Australasian Ciillcijc of, SyiJ(rcj. May. 1^79.

tt IX-rrnatofogy•* I'lioioihcrapy Nurse,AOiltcss (in icprinis: Dr. tl. HoisleJii, 13 (."oDimSirefi, Mclbourni;,

Vic. 3000.

Staging: On the basis of data presented bySamman." patients 1 to 9 were considered tohave early M.F., and patients 10 lo 20 a moreadvanced disease.

Laboratory testing performed as a routine wasfull blood examination, liver function tests, elec-trolyles and urea, and chest x-ray. Palpablenodes were biopsicd. Liver-spleen scan was per-formed if liver or spleen were palpable. Liverbiopsy was performed if the liver was enlarged orliver function tests were abnormal. Bone marrowaspiration and trepliinc were performed if cir-cukaing iib(iorrT?al colls were noted on full bloodexamination.

Light Source: Patients were treated whilestanding in a six-sided boolh with each side con-taining eight six-foot long vertically orientedGeneral Electric high outpui black light tubes,the emission characteristics of which havepreviously been described." Irradiance was deter-nilnetl using an Internationa! Light Cor(X)ration1L442 light meter with a diode receiving headhaving a wide acceptance angle.

Dosages: 8-nietlioxypsoralon (approximately0.6 mg/kg) was taken orally (wt) hours prior toullraviolcl lighl exposure and this dosai^e re-mained unchanged during treatment. InitialUVA exposure was on the basis of history ofsunburning tendency am! pigmenting ability, aspreviously described for treatment of psoriasis.'"Ultraviolet light exposure was initially given

MYCOSIS FUNGOIDES AND P U V A 101

TABLE 1

PARAHETERS AT

PATIENT CLINICALNUMBER. PATUHN.

1.

2.

3,

4.

S.

6 .

7.

8.

9.

10.

1 1 .

2.

13.

14.

IS.

16.

n.

IB.

19.

20.

Poiki lodcrma

Pol H lodennj

Po^Vi loflerma

PalMlo^nn.

Polklloderma

PolkUodenM

Erythematouspatches

Erythematous

Erythema LOUS

Plaques

Plaques

Ptaquei

Plaques

- - ' -

Nodules

Nodules

ErytttrodennaS adenopathy

Erythrodenna1 idenopathy

[rythroderma% a den op a thy

Erythrn derma

ACE/SE«.

20/F

43/F

« ; .

6 7/M

4e/M

71/F

23/F

6S/H

.8 /F

6B/F

37/F

7S/H

?0/F

43/F

60/M

55/W

77/M

4B/F

68/M

CO»»CNCtMEN

PROBASLEDUAAIION

OF OlStASE.

* years

20 years

4 years

10 ,e»r\

2,e. rs

10 >e»ri

7 years

6 months

2\i years

8 years

10 ye»rt

5 years

IB years

J y«ar«

10 years

10 years

* ye*r»

11 months

10 years

8 years

OF PUV*

TIME FROMHISTOLOGICAL

DIAGNOSIS.

3 nunths

14 years

2 months

1 monttv

^"^"^^

\ ircnth

1 month

4 months

6 years

7 months

? months

2 months

3 nonttis

1 year

S rwivlhi

4 nontfts

9 months

b years

years

PRIORTREAIMENI,

topical

SKRT and

n i l

taptealsteroid

topicalSteroid

topicalsteroid

topical

oral steroids

-icertaln

electron besm

topicalsteroid

topicalsteroidU.V.B.

S«RT I oralmethotreiate

topicalSteroid

5<RT

theino therapy

steroid*oral andtopical

topicalsteroid

systemicchemotherapy

systemic

[. beamLeuliaphiiresis

NUMBIR OFIBtATMEHtSTO COMPLETIRAPID PHASE.

not reached

17

36

12

30

20

2a

33

not reacJied

39

37

not reached

1?

not reached

2 ]

se

not reached

RESPONSE TO PUVA

CUMULAlIVtDOSE UVftOURINCISTUOr PERIOD

93.S

671

7^6.5

4Z5

605

64S

195

919

IS3

813.5

19S6

1531

21?.5

64 3

1716

1.0

1294

458.5

10.S

AOJUVANITREftTM.HlUSED DURINIIPLJVA.

n i l

n i l

n i l

n i l

local izednitrogenmustard

n t i

steroid

topicalsteroid

n i l

n i l

n l )

whole bodytopicalmustard

localiiedtopicalinus t a rd

n i l

SIRT

hyflroiy ureatcpicatthiotepa

steroids o ra land topical

n i l

systemicchew) therapy

systemicchemotherapy

CLINICAL CLEARINGKAlHTftlHtO W r PUVft̂

no - wl thdrew (romtreatment (unstablepersonality).

^ts fo^ 3 ffonlhs.

yes for 4 monthsnot yet retreated.

yes for a months.

yes fQi" 2 rtmlhsnot yet retreated.

no.

yes for 3 rfonths.

r o .

no.

no - withdraw fromtreatment (painfulukers) .

no.

no.

no.

no - Mllhtfrew fromtreatment (pregnancy)

yes for Z monthsehanjed to whole bodytopical "lustard.

no.

no - withdrew fromtreatment (alcohol)

no.

no - patient died.

no - patient died.

102 H . ROTSTEJN ET Al-

twice p&r week, and increased by 0.50.5 J/cm^ ateach treatment unless erythema was noted.

It was quickly reiilized that in each patient astage WHS reached where further improvementcontinued but could not be hastened by furtherincreasing UVA dose or frequency. The time ittook to reach this stage varied for each patientbut was easily recognized and it was then thatthe UVA dose was held constant and the fre-quency of treatment reduced.

Assessmeni of Progress: Reference was madeat each visit to photographs taken at presenta-tion and to charts hand drawn at frequent inter-vals. Repeat biopsies were taken when the skinappeared elear or when there were areas ofminimal residual change that were ihought notto contain cells of M.F. Patients were reviewedevery four lo eight weeks for clinical evidence ofextracutaneous involvement. Laboratory assess-ment of spread was performed every six mouthsand chest x-ray examination every twelvemonths. We reviewed.Ihe patients in conjunctionwith the oncologists on presentation and onceper year or more often if there was any doubtregarding exlracutaneous spread.

RESULTS

The skin manifestations in all patientsimproved with treatment. There was no doubtIhat treatment was responsible for improvement.Occasionally in patients otherwise clear, regionsshielded from ultraviolet light for anatomicalreasons (such as upper medical aspect of thighand gluteal folds) developed lesions of M.F. thatcould be cleared by simply ensuring adequateexposure at subsequent treatments. Superficialx-ray therapy was used to treat a small plaque ofM.F. on the upper inner thigh of one patientbecause adequate ultraviolet light exposure ofthis area could not be achieved. The plaqueresolved uneventfully.

The clinical response in most cases followed atypical pattern of early rapid improvement fol-lowed by a stage of improvement at a slowerrate. It appeared that once this second stage wasreached the response could not be enhanced byincreasing exposure dose or frequency. Therapidity of response could not be correlated withpattern o[ cUn'tca} prcscnlal'ion.

if cutaneous M.F. reappeared, it usually did soat a time when treatments were given less fre-quently than once per week. Simply treatingmore frequently without any change in Iheexposure dose of UVA or psoralen dosage could

again produce resolution. Resistance to thiseffect of PUVA did not occur.

Cutaneous manifestations of M.F. improvedgreatly in all patients regardless of the initialpaUcrn of presentation. However, careful exami-nation of all patients who considered themselvesclear would reveal areas (not only in ultravioletlight-shielded regions) where the skin was notquite normal. These minor signs were slightepidermal atrophy, faint erythema, minimal in-duration, faint pallor and telangiectatic spots.These occurred either singly or in combination.Biopsy of these areas invariably revealed mycosisfungoides on light microscopy examination.When normal-looking skin from an area pre-viously involved was re biopsied the histology ofM.F. was also found. The infiltrate in the upperdermis was less dense than in the original biopsyand epidermal involvement was uncommon.

All patients considered clinically cleareventually developed recurrence of cutaneousmanifestations. The clinical pattern of recurrencewas usually recognized as minimally infiltratedareas or papules.

In two patients, urticaria! papules arranged incurved and linear clusters came and wentbetween PUVA treatment on areas consideredclinically to be free of M.F. These papules werediagnosed clinically as insect bites but biopsyshowed cells with convoluted nuclei in thedermis and one patient also had these cellspresent in clusters within the epidermis.

In those patients considered to have M.F.confined to the skin before commencingtreatment, evidence of extracutaneous spreadwas not noted subsequently. However, thefollow-up period is extremely short and ante-niortem assessment of extracutaneous involve-ment is unreliable. Two patients withextracutaneous disease died. They had beenreceiving systemic chemotherapy as well. Onepatient died at iiome. The other died of anoverwhelming varicella infection and at post-mortem no evidence of mycosis fungoides wasfound. One patient with erythroderma andenlarged nodes was an unreliable attender,ceased treatment and was lost to follow-up. Theoiher piit'icnl with erylhrodcrma and enlargedlymph nodes had a reduction in size of lymphnodes and clearing of erytliroderma produced byPUVA alone. Initial biopsy showed dermato-pathicadenopathy with a small collection of cellswith deeply cleft nuclei seen in the marginal

MYCOSIS FUNGOIDES AND PUVA 103

sinus on electron microscopy. Repeat nodebiopsy has not been performed.

COMPLICATIONS

Generalized itch, blisters on the dorsa of thefeet and also activation of herpes simplexinfeclioa, previously described complications ofPUVA used to treat psoriasis, were seen butthese were of minor concern and resolvedquickly. In some patients areas of M.F. becameerytliematous and tender without other asso-ciated changes being present. Tliis ustiallyhappened early in the course of treatment fol-lowing a large increase in UVA dose and il wasfelt that these areas probably representedPUVA-induced erythema even though normallooking skin was not affected. The erytliemawould resolve in seven to ten days if all treat-meni was withheld.

One patient developed a cercbro-vascular acci-dent four days after a myocardia! infarct com-plicated by cardiac failure and ventricularectopic beats. A C A T . scan showed an area ofreduced density in the left posterior parietal andleft occipital lobes. It was felt that this was due toan embolus from an endocardia! tlirombus due tohis myocardial infarction.

The theoretical complications of eye toxicity"and neoplastic change'- were not seen. However,one patient showed clinically aged skin especiallyon the dorsa of the hands with marked elastoticchange present on biopsy of abdominal skin.

One patient developed painful ulceration with-in plaques and this was attributed to priorelectron beam therapy.' This settled with con-servative treatment and shielding from UVexposure during treatments. Subsequent PUVAtherapy did not again produce ulcers.

DISCUSSION

All patients improved with PUVA therapyand there was no difference in this regardbetween patients with early M.F. (consideredeither as clinical pattern or short duration ofdisease), and those with advanced M.F. How-ever, using histology and a clinical course asguides to progress, a cure could not be obtained.

PUVA seemed to be an excellent means oi' pallia-tion of the signs and symptoms of cutaneousM.F. It could be suggested that a cure was notachieved because treatment was not aggressiveenough but the reasons we chose a less aggressiveapproach were: improvement of the skin in

patients with M.F. does not alter their long-termprognosis;" the cells of M.F. may not originate inthe skin,'*-" as once thought; large cumulativedoses of UVA necessary would increase thepossibility of carcinogenesis in patients having adisease in whieli long term survival is possible.

Because the long-term course iti these patientsimplies apparent microscopic persistence of M.F.and because resistance to PUVA if reinstitutcdwas not noticed, it is suggested that PUVA beused to bring cutaneous M.F. to the stage ofapparent maximal improvement; PUVA shouldthen be ceased even if histology indicatespersistetice of M.F. and the patients followedclosely. Should clinical features of cutaneousM.F. recur, treatment with PUVA or otherappropriate therapy should be recommenced.

Although aggressive treatment has beenadvocated by those who consider M.F. acutaneous lymphoma which may involveinternal organs,' ' '^ watchful waiting andtreatment when necessary is an accepted effec-tive method of treatment in certain well-definednon-Hodgkin's iyniphomas'^' '"and this approachto treatment of M.F. has produced excellent sur-vival figures in certain clinically recognizableforms of M.F. in the past."

Although PUVA is an effective method ofcausing regression of cutaneous deposits of M.F.it would not appear to be curative.

ACKNOWl.bDG[-MHNTS

This work was performed while we were mem-bers of the staff of the Dermatology Unil of St.Vincent's Hospital. Melbourne. We are indebtedto the liospital authorities for permission topublish.

We also wish to acknowledge the assistanee ofDr. John Heggie. physicist at St. Vincent'sHospital; Protea Pharmaceuticals who supplied8-methoxypsoralen; and the Melbourne derma-tologists who referred patients for treatment.

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