Cutaneous T-cell lymphoma: molecular pathogenesis and clinical behaviour. Doorn, R. van

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Cutaneous T-cell lymphoma: molecular pathogenesis and

clinical behaviour.

Doorn, R. van

Citation

Doorn, R. van. (2005, October 26). Cutaneous T-cell lymphoma: molecular

pathogenesis and clinical behaviour. Retrieved from

https://hdl.handle.net/1887/3630

Version:

Corrected Publisher’s Version

License:

Licence agreement concerning inclusion of doctoral

thesis in the Institutional Repository of the University

of Leiden

Downloaded from:

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Chapter 2 Mycosis fungoides: disease evolution and

prognosis of 309 Dutch patients

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Mycosis Fungoides

Disease Evolution and Prognosis of 309 Dutch Patients

Remco van Doorn, MD; Christian W. Van Haselen, MD; Pieter C. van Voorst Vader, MD;

Marie-Louise Geerts, MD; Freerk Heule, MD; Menno de Rie, MD; Peter M. Steijlen, MD;

Sybren K. Dekker, MD; Willem A. van Vloten, MD; Rein Willemze, MD

Objectives:

To determine the disease course of Dutch

patients with mycosis fungoides and to define factors

re-lated to disease progression and survival.

Design:

A multicenter, 13-year, retrospective cohort

analysis.

Setting:

Eight dermatology departments collaborating

in the Dutch Cutaneous Lymphoma Group.

Patients:

Three hundred nine patients with mycosis

fun-goides registered between October 1985 and May 1997,

in-cluding 89 patients with limited patches or plaques (stage

Ia), 135 with generalized patches or plaques (stage Ib), 46

withskintumors(stageIc),18withenlargedbutuninvolved

lymph nodes (stage II), 18 with lymph node involvement

(stage III), and 3 with visceral involvement (stage IV).

Main Outcome Measures:

Response to initial

treat-ment, sustained complete remission, actuarial disease

pro-gression, and overall and disease-specific survival per

clini-cal stage.

Results:

The median follow-up was 62 months (range,

1-113 months). For the entire group, the actuarial

over-all and disease-specific survival was 80% and 89% at 5

years, and 57% and 75% at 10 years, respectively. The

actuarial 5-year disease-specific survival of patients

with stage Ia, Ib, and Ic disease was 100%, 96%, and

80%, respectively, and only 40% for patients with stage

III disease. Using multivariate analysis, the presence of

extracutaneous disease, the type and extent of skin

in-volvement, the response to initial treatment, and the

presence of follicular mucinosis were independently

as-sociated with higher disease progression and mortality

rates. The calculated risks of disease progression at 5

and 10 years gradually increased from 4% to 10% for

those with stage Ia disease, from 21% to 39% for those

with stage Ib disease, and from 32% to 60% for those

with stage Ic disease; for those with stage III disease, the

risk remained at 70% at 5 and 10 years. The overall risk

of disease progression at 5 and 10 years was 24% and

38%, respectively, for the total study group.

Conclusion:

At least within the first 10 years after

di-agnosis, disease progression and mycosis fungoides–

related mortality occur in only a subset of patients

gen-erally presenting with advanced disease.

Arch Dermatol. 2000;136:504-510

M

YCOSIS

fungoides (MF)

is the most common

type of cutaneous

T-celllymphoma(CTCL),

with an estimated

in-cidence of 0.5 per 100 000 per year in the

western world.

1

_{According to the major}

textbooks, MF is an indolent type of CTCL

that slowly evolves through patch, plaque,

and tumor stages before lymph nodes and

visceral organs become involved, and

ul-timately a rapidly progressive and fatal

dis-ease develops. Long-term follow-up

stud-ies

2-14

_{on large groups of patients with MF}

are rare, and most come from a few

US-based centers. Comparison of published

series is often difficult, because of

differ-ent inclusion criteria (eg, inclusion or

ex-clusion of patients with large-plaque

para-psoriasis) and an inconsistent use of the

terms MF and CTCL. Several studies,

in-cluding one of the largest European

stud-ies of 92 Dutch patients published by

Ham-minga et al

4

_{in 1982, included not only}

patients with classic MF but also patients

with Se´zary syndrome and other types of

CTCL defined more recently. For

in-stance, patients with CTCL presenting with

tumors with the histological appearance

of a diffuse, large, T-cell lymphoma and

without prior or concurrent patches or

plaques were designated previously as

hav-ing “MF d’emble´e,” whereas such

pa-tients are now classified as having either

CD30

+

_{or CD30}

−

_{large-cell CTCL, which}

are considered distinct disease entities

sepa-rate from MF.

15,16

It is well recognized that the

evolu-tion from skin-limited to widespread

dis-seminated disease in patients with MF may

take years or even decades. However,

clini-cal experience also suggests that only a

pro-portion of patients with MF presenting with

only skin lesions will develop

extracuta-STUDY

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neous and ultimately fatal disease. Whereas previous

stud-ies mainly focused on prognostic variables and survival

data in the different stages of MF, data regarding the

fre-quency of disease progression have been published only

recently.

10-13

_{Obviously, clinical information to patients with}

MF should not only include the message that disease

pro-gression may occur but also how often and after which

pe-riod such a development can be expected.

In the present study, clinical and follow-up data of all

patients with MF included between October 1985 and May

1997 in the registry of the Dutch Cutaneous Lymphoma

Group were evaluated. This study determines

disease-specific and overall survival and the risk of disease

pro-gression for patients with different stages of MF and

de-fines variables predictive of survival and disease progression.

RESULTS

CLINICAL CHARACTERISTICS AT PRESENTATION

Of the 309 patients included in this study, 72.5% had

ei-ther stage Ia or Ib MF at the time of diagnosis, whereas

PATIENTS AND METHODS

Between October 1985 and May 1997, 345 patients with MF

were included in the registry of the Dutch Cutaneous

Lym-phoma Group, and follow-up data had been collected yearly.

For the present study, only patients with clinical and

histo-logical features consistent with MF, and who underwent a

follow-up period of at least 12 months after histological

con-firmation of the diagnosis, unless death due to MF

oc-curred earlier, were selected. Thirty-six patients were

ex-cluded because of insufficient clinical information or

follow-up. The final study group comprised 309 patients. In each

patient, the diagnosis had been made by an expert panel of

dermatologists and pathologists at 1 of the quarterly

meet-ings of the Dutch Cutaneous Lymphoma Group. The

his-tological criteria for the diagnosis of early MF are

essen-tially the same as those described by Nickoloff,

17

_{and require}

the presence of hyperchromatic, slightly to markedly

atypi-cal lymphoid cells in the epidermis, either as single, often

haloed, cells, or in a linear configuration at the

dermal-epidermal junction. Patients with patches or plaques

clini-cally suspected, but histologiclini-cally not diagnostic of MF, are

included as a separate category in the Dutch registry and were

not included in the present study, unless at a later point a

definite diagnosis of MF was made. The time of the first

di-agnostic biopsy was taken as the time of diagnosis. The study

group did not include patients with Se´zary syndrome,

pag-etoid reticulosis, or other CTCL, recognized as distinct

en-tities in the European Organization for Research and

Treat-ment of Cancer classification for primary cutaneous

lymphomas.

16

_{However, to allow comparison with other}

pub-lished series, patients with MF-associated follicular

muci-nosis, included as a distinct variant of MF in the European

Organization for Research and Treatment of Cancer

classi-fication, were included. Association with follicular

mucino-sis was included as one of the variables in univariate and

mul-tivariate analyses of survival and disease progression.

The stage of the disease was determined based on the

type and extent of skin involvement and the presence of

lymph node, visceral, or blood involvement according to

a modification of the Fuks classification scheme,

4,18

_which

can easily be translated into the TNM system

19

₍

_{Table 1}

_).

Staging evaluation consisted of obtaining a complete

medi-cal history and a complete blood cell count and

perform-ing a physical examination, serum chemistry studies, and

a skin biopsy. In the presence of lymphadenopathy, a lymph

node biopsyand thoracic and abdominal computed

tomo-graphic scans were performed, and a chest x-ray film was

obtained. Lymph node involvement was assessed

through-out the study (1985-1997) with the same criteria,

de-scribed previously.

20

_{When indicated clinically,}

addi-tional staging studies to determine visceral involvement were

performed. The following variables were recorded: age; sex;

clinical stage at the time of diagnosis; duration of skin

le-sions before diagnosis; type of initial therapy; whether there

was complete remission after initial therapy; disease course

after initial therapy; the date of disease progression, if

ap-plicable; and the date of last contact and cause of death, if

applicable. In addition, the presence of follicular

mucino-sis in the first diagnostic biopsy specimen and the

pres-ence of lymphomatoid papulosis or B-cell neoplasms prior

to, concurrent with, or following the development of MF

were recorded. Complete remission on initial treatment was

defined as complete disappearance of all skin lesions. In

most cases, histological confirmation of complete

remis-sion was not obtained. No distinction was made between

partial or no responses on initial therapy. For clinical course,

distinction was made between sustained complete

remis-sion, defined as the total disappearance of all (extra)

cuta-neous lesions after initial therapy without subsequent

relapse (without maintenance treatment); continued

dis-ease, disease without progression to a higher clinical stage;

and disease progression, the development of skin tumors in

patients with a previous patch or plaque (stage Ia-Ib), the

development of histologically documented nodal

involve-ment (stage III) in patients with previous skin-limited

dis-ease, the development of visceral involvement in patients

with prior skin and/or lymph node involvement, and death

due to MF.

As indicators of survival, disease-specific survival,

in-cluding only death related to MF as the event, and overall

survival, including death due to any cause as the event, were

investigated. Actuarial survival and disease progression curves

were calculated from the date of diagnosis to the date of death

or last contact and the date of disease progression,

respec-tively, using the Kaplan-Meier technique.

21

_{Patients lost to}

follow-up were considered to be censored at the time of last

contact. Differences between survival and disease

progres-sion rates were analyzed using the log-rank test.

Compara-tive analysis of groups of numerical variables was

per-formed using 2-tailed t tests. P.05 was considered

significant. Relative risks and 95% confidence intervals were

determined using standard methods. Univariate analysis of

possible prognostic factors was performed using the

log-rank test and Cox proportional hazards regression analysis.

Multivariate analysis was performed by entering significant

univariate variables for survival and disease progression in

Cox proportional hazards regression analysis

22

_{to establish}

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14.9% presented with 1 or more skin tumors in

addi-tion to patches and plaques, but no evidence of

extracu-taneous disease. Of the 309 patients, 270 (87.4%) had

only skin lesions at the time of diagnosis; 18 (5.8%),

en-larged but histologically uninvolved lymph nodes; and

21 (6.8%), nodal and/or visceral involvement (

Table 2

).

Considering the entire group of patients, the age at

diagnosis varied between 14 and 92 years (median, 61

years). Only 2 patients (0.6%) were younger than 20 years

at the time of diagnosis. Patients presenting with stage

Ic MF were significantly older than patients with stage

Ia MF (67.5 vs 58.0 years; P.001). There was a male

predominance, with a male-female ratio of 196:113, which

is consistent with that of other large series.

2,3,13

_The

du-ration of skin lesions before a definite diagnosis could

be made varied between 1 month and more than 50 years

(median, 48 months) and was significantly shorter in the

21 patients presenting with extracutaneous disease

(me-dian, 24 months) compared with patients with only skin

lesions at presentation (median, 48 months) (P = .006).

Of the 309 patients with MF, 32 (10.4%) had

asso-ciated follicular mucinosis at the time of diagnosis. This

Table 1. Clinical Stage of 309 Patients With MF at the Time of Diagnosis*

Stage

Patches and Plaques Covering the Skin Surface

Skin

Tumor (c) Erythroderma (d) Total

10% (a) 10% (b)

MF confined to the skin (I) 89 135 46 0 270

MF with dermatopathic lymphadenopathy (II) 0 9 7 2 18

MF with lymph node involvement (III) 1 7 8 2 18

MF with visceral involvement (IV) 0 0 3 0 3

Total 90 151 64 4 309

*The clinical stage is given according to the modified Fuks classification.4_{Translation into the TNM classification}18_{is as follows; Ia, T1 N0 M0; Ib, T2 N0 M0;}

Ic, T3 N0 M0; Id, T4 N0 M0; IIa through IId, T1 through T4 N1 M0; IIIa through IIId, T1 through T4 N3 M0; and IVa through IVd, T1 through T4 N0 through N3 M1. MF indicates mycosis fungoides.

Table 2. Patient Characteristics and Disease Outcome per Clinical Stage*

Variable Stage All Ia Ib Ic II III IV No. of patients† 89 (28.8) 135 (43.7) 46 (14.9) 18 (5.8) 18 (5.8) 3 (1.0) 309 (100) Age at diagnosis, median (range), y 58.0 (19-90) 61.0 (14-92) 67.5 (35-88) 62.5 (37-82) 57.5 (29-84) 67.0 (53-69) 61.0 (14-92) Male-female ratio 59:30 83:52 29:17 10:8 13:5 2:1 196:113 Duration of skin lesions before diagnosis, median (range), mo 60 (1-372) 48 (1-600) 48 (2-600) 48 (10-648) 24 (5-300) 24 (10-72) 48 (1-648) Complete remission on initial therapy 42 (47) 41 (30) 12 (26) 2 (11) 1 (6) 0 (0) 98 (32) Duration of follow-up, median (range), mo 71 (12-203) 70 (12-313) 48 (6-249) 45 (14-184) 49 (8-239) 2 (1-9) 62 (1-313) Disease course Sustained CR 16 (18) 10 (7) 5 (11) 1 (6) 1 (6) 0 (0) 33 (11) Continued disease 69 (78) 92 (68) 23 (50) 8 (44) 6 (33) 1 (33) 199 (64) Progression 4 (4) 33 (24) 18 (39) 9 (50) 11 (61) 2 (67) 77 (25)

Risk of disease progression, %

At 5 y 4 21 32 65 70 100 24

At 10 y 10 39 60 65 70 . . . 38

Current status

Alive without disease 39 (44) 29 (21) 5 (11) 1 (6) 1 (6) 0 (0) 75 (24)

Alive with disease 41 (46) 71 (53) 14 (30) 10 (56) 5 (28) 0 (0) 141 (46)

Died of other cause 7 (8) 22 (16) 12 (26) 4 (22) 1 (6) 1 (33) 45 (15)

Died of MF 2 (2) 13 (10) 15 (33) 3 (17) 11 (61) 2 (67) 47 (15) Disease-specific survival, % At 5 y 100 96 80 68 40 0 89 At 10 y 97 83 42 68 20 0 75 Overall survival, % At 5 y 99 86 65 49 40 0 80 At 10 y 84 61 27 49 20 0 57

*Data are given as number (percentage) of patients within each column unless otherwise indicated. Percentages may not total 100 because of rounding. The clinical stages are explained in Table 1. CR indicates complete remission; MF, mycosis fungoides; and ellipses, data not applicable.

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group included 28 patients with stage I, 3 with stage II,

and 1 with stage IV MF. The combination of MF—stage

Ia in 2 and Ib in 6 patients—and lymphomatoid

papu-losis was noticed in 8 (2.6%) of the 309 patients.

Asso-ciated B-cell lymphoproliferations were documented in

5 patients with stage Ia or Ib MF, including 4 with B-cell

chronic lymphocytic leukemia and 1 with nodal

follicu-lar lymphoma.

TREATMENT AND FOLLOW-UP

The initial therapies at the different stages of MF are listed

in

Table 3

, and reflect the approach used in the

treat-ment of MF in the Netherlands. The treattreat-ment modality

most commonly used for stage Ia or Ib disease was

pso-ralen–UV-A therapy (140 [62.5%] of 224 cases); less

frequently used modalities included topical

corticoste-roids, UV-B therapy, topical mechlorethamine

hydro-chloride, and, in case of extensive skin lesions, total skin

electron beam irradiation. Patients with stage Ic disease

were treated similarly, often with additional local

radio-therapy for persistent tumors (Table 3). Systemic

poly-chemotherapy consisting of cyclophosphamide,

vincris-tine sulfate, doxorubicine, and prednisone was mainly

given to patients presenting with nodal (stage III) or

vis-ceral (stage IV) involvement, often in combination with

or followed by skin-directed therapies.

Initial treatment resulted in clinical complete

re-missions in 98 (31.7%) of 309 patients. However, in most

patients, these complete remissions were short-lived.

Sus-tained complete remissions on initial treatment were

ob-served in only 33 (10.7%) of the 309 patients, among

whom 26 had stage Ia or Ib disease. The disease-free

sur-vival in these 33 patients varied between 10 and 163

months (median, 68 months). In 199 (64.4%) of the 309

patients, there was continued disease without

progres-sion, typically having a fluctuating course, while in the

remaining 77 (24.9%), disease progression, including

death due to MF, occurred.

The median follow-up was 62 months (range, 1-313

months). During that period, 92 of the 309 patients died,

including 47 of MF. The disease-specific survival at 5 and

10 years for the whole group of 309 patients was 89%

and 75%, respectively; the 5- and 10-year overall

sur-vival was 80% and 57%, respectively. The sursur-vival rates

according to clinical stage are presented in Table 2,

Figure 1

, and

Figure 2

. Consistent with prior

re-ports,

23,24

_{patients with MF and lymphomatoid}

papulo-sis had an excellent prognopapulo-sis. None of these patients

showed disease progression after a median follow-up of

158 months (range, 23-244 months).

PROGNOSTIC VARIABLES

Univariate analysis of variables possibly influencing

dis-ease-specific survival in the entire group of 309 patients

showed that the following factors were statistically

sig-nificant: stage at diagnosis (P.001), including the

pres-ence of extracutaneous disease (P.001) and the type and

extent of skin involvement (P.001); no complete

re-mission on initial treatment (P.001); associated

fol-licular mucinosis (P = .005); and older age (P = .01). Sex

(P = .69) and duration of skin lesions before diagnosis

(P = .34) were not significantly related to survival, when

the total group was considered.

Univariate analysis of the prognostic variables per

clinical stage showed that only complete remission on

initial treatment within the group of patients with stage

Ib MF was significantly related to survival (P = .04)

(

Figure 3

). Multivariate analysis revealed that—in

or-der of predictive value—presence of extracutaneous

dis-ease, type and extent of skin involvement, no complete

response to initial treatment, and presence of follicular

mucinosis were independently associated with

MF-related mortality. The relative risks for MF-MF-related

mor-tality are presented in

Table 4

.

Regarding clinical stage, patients with stage Ia and

stage Ib MF had a significantly better survival than

pa-tients with stage Ic MF (P.001). However, no

signifi-cant difference in survival was found between patients

with stage Ia and stage Ib disease (P = .11). Notably, not

only patients with histologically documented lymph node

involvement (stage III) but also patients with enlarged,

but histologically uninvolved, lymph nodes (stage II) had

Table 3. Initial Treatment per Clinical Stage*

Initial Treatment Stage All (N = 309) Ia (n = 89) Ib (n = 135) Ic (n = 46) II (n = 18) III (n = 18) IV (n = 3) Topical corticosteroids 15 (17) 11 (8) 0 0 0 0 26 (8) PUVA therapy 51 (57) 89 (66) 9 (20) 7 (39) 0 0 156 (51) UV-B therapy 14 (16) 15 (11) 0 0 0 0 29 (9)

Topical mechlorethamine hydrochloride 6 (7) 10 (7) 4 (9) 0 1 (6) 0 21 (7)

Total skin electron beam irradiation 0 7 (5) 6 (13) 1 (6) 4 (22) 0 18 (6)

Radiotherapy with or without skin-directed therapy† 3 (3) 2 (2) 21 (46) 5 (28) 2 (11) 1 (33) 34 (11)

Polychemotherapy with or without skin-directed therapy 0 0 4 (9) 2 (11) 10 (56) 2 (67) 18 (6)

Other‡ 0 1 (1) 2 (4) 3 (17) 1 (6) 0 7 (2)

Complete remission on initial treatment, % 47 30 26 11 6 0 32

*Data are given as number (percentage) of patients unless otherwise indicated. Column percentages may not total 100 because of rounding. The clinical stages are explained in the footnote to Table 1. PUVA indicates psoralen–UV-A.

†Skin-directed therapies include topical corticosteroids, PUVA therapy, UV-B therapy, topical mechlorethamine hydrochloride, radiotherapy, or total skin electron beam irradiation.

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a significantly lower survival compared with patients with

stage I MF (P.001 and P = .02, respectively).

DISEASE PROGRESSION

One of the goals of this study was to assess the risk of

disease progression, including death due to MF, for

pa-tients with different stages of MF. The calculated risks

of disease progression at 5 and 10 years gradually

in-creased from 4% to 10% for those with stage Ia disease,

from 21% to 39% for those with stage Ib disease, and from

32% to 60% for those with stage Ic disease; for those with

stage III disease, the risk remained at 70% at 5 and 10

years (Table 2).

Table 5

shows the actual frequency of

disease progression in the group of 309 patients after a

median follow-up of 62 months. It also shows that the

higher the clinical stage at diagnosis, the shorter the

du-ration until disease progression.

Multivariate analysis revealed that—as for

disease-specific survival—the presence of extracutaneous

dis-ease, the type and extent of skin involvement, the

re-sponse to initial treatment, and the presence of follicular

mucinosis were independently associated with disease

progression.

COMMENT

In the present study, the main clinical characteristics,

dis-ease evolution, and survival of 309 Dutch patients with

MF, included in the Dutch registry for cutaneous

lym-phomas between October 1985 and May 1997, were

evalu-ated. In addition, prognostic variables and the risk of

dis-ease progression for those with different stages of MF were

analyzed. The median age at diagnosis of 61 years and

the male-female ratio of 196:113 were similar to those

given in the few other large series studied.

2,3,13

_{At the time}

of first presentation, 93.2% of the patients with MF had

only skin lesions, including 5.8% with concurrent

en-100 80 60 40 20 0 60 120 180 Follow-up Duration, mo Sur vival, %

Patients With Stage I MF (n = 270) Patients With Stage II MF (n = 18) Patients With Stage III MF (n = 18) Patients With Stage IV MF (n = 3)

Figure 1.Actuarial disease-specific survival of 309 patients with mycosis fungoides (MF). The differences between the patients with each stage of MF are as follows: stage I vs stage II,P= .02; stage I vs stage III,P.001; stage II vs stage III,P= .13; and stage III vs stage IV,P.001.

100 80 60 40 20 0 60 120 180 Follow-up Duration, mo Sur vival, %

Patients With Stage Ia MF (n = 89) Patients With Stage Ib MF (n = 135) Patients With Stage Ic MF (n = 46)

Figure 2.Actuarial disease-specific survival of 270 patients with stage I mycosis fungoides (MF). The differences between the patients with each variation of stage I MF are as follows: stage Ia vs stage Ib,P= .11; stage Ia vs stage Ic,P.001; and stage Ib vs stage Ic,P.001.

100 80 60 40 20 0 60 120 180 240 Follow-up Duration, mo Sur vival, %

Patients With Complete Remission (n = 41) Patients Without Complete Remission (n = 94)

Figure 3.Actuarial disease-specific survival of patients with stage Ib mycosis fungoides with or without complete remission after initial treatment. The difference between those with complete remission vs those without complete remission was significant (P= .05).

Table 4. Factors Independently Influencing

Disease-Specific Survival*

Factor RelativeRisk 95% ConfidenceInterval P

Extracutaneous involvement

I (absent)† 1.0 . . . . II (LN enlargement) 3.3 1.1-9.5 .02 III (LN involvement) 7.3 3.6-14.8 .001 IV (visceral involvement) 227.0 31.3-1646.3 .001 Type and extent of skin lesions

Ia (limited plaques)† 1.0 . . . . Ib (generalized plaques) 3.2 0.7-14.4 .11 Ic (skin tumors) 20.9 4.7-92.0 .001 Complete remission after

initial treatment Yes† 1.0 . . . . No 7.0 2.2-22.5 .001 Follicular mucinosis Absent† 1.0 . . . . Present 2.3 1.1-5.0 .001 *Factors are presented in order of predictive value. The relative risk of different types and extents of skin lesions has been calculated for stage I only. LN indicates lymph node; ellipses, data not applicable.

†Referent value.

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larged but histologically uninvolved lymph nodes, whereas

only 6.8% presented with concurrent nodal or visceral

involvement.

In the Netherlands, patients with MF are treated

tra-ditionally with skin-directed therapies, including

topi-cal corticosteroids, psoralen–UV-A therapy, UV-B therapy,

or topical mechlorethamine hydrochloride, and

addi-tional radiotherapy in case of concurrent skin tumors,

whereas multiagent chemotherapy is generally only used

in patients with extracutaneous localizations. Initial

treat-ment according to this classic approach resulted in a

com-plete remission in almost one third of the patients (98

of the 309 patients). As expected, in most patients, this

complete remission was short-lived. However, in 33 (34%)

of the 98 patients achieving complete remission on

ini-tial treatment, and not receiving any type of

mainte-nance treatment, there was no subsequent relapse.

Eigh-teen of these 33 patients, including 9 with stage Ia, 5 with

stage Ib, 3 with stage Ic, and 1 with stage IIb MF, have

been in complete remission for more than 5 years, and,

since most relapses occur within 5 years after achieving

complete remission,

10,13

_{may be considered as potential}

cures. The present retrospective study does not allow a

representative comparison of the effects of the different

treatment modalities, since treatment selection may have

been affected by disease severity. It is, therefore, not

sur-prising that we did not find a relation between the

re-sults of initial treatment and the type of treatment given

(data not shown). The complete response of only 10

(55.6%) of the 18 patients to total skin electron beam

ir-radiation at initial therapy may be explained by the fact

that 4 of 18 patients had stage III disease, and 8 of the

14 remaining patients had MF-associated follicular

mu-cinosis, a combination known to be rather refractory to

total skin electron beam irradiation.

25

The disease-related and overall survival for the

whole group of 309 patients was 89% and 80% at 5

years, and 75% and 57% at 10 years, respectively. For

the survival rates for the different stages of MF, the

over-all and disease-specific survival rates at 5 and 10 years

for patients with stage Ia and Ib MF (Table 2) were

simi-lar to those reported in previous studies.

4,5,10-14

_{In this}

study, we did find a difference in survival between those

with stage Ia and those with stage Ib MF, but this did

not reach statistical significance. The fact that disease

progression was much more frequent in patients with

stage Ib MF than in those with stage Ia MF suggests that

with longer follow-up, the difference in survival might

become statistically significant.

Our study did not include patients with

large-plaque parapsoriasis, characterized by the presence of

patches or slightly infiltrated plaques but with

histologi-cal changes not diagnostic of MF. While we consider such

lesions as a potential precursor of MF, other groups

26

_have

expressed the view that large-plaque parapsoriasis, and

even small-plaque parapsoriasis, should be considered

as MF, and not as precursors of MF. However, in view

of the excellent prognosis of patients with stage Ia MF—

similar to that of a race-, age-, and sex-matched control

population

10

_{—and the low tendency to progress, it is}

ques-tionable which patient with small-plaque parapsoriasis

will benefit from being marked as a patient with CTCL.

Because of this ongoing controversy and the

inconsis-tent use of the terms large-plaque parapsoriasis and

small-plaque parapsoriasis, it is perhaps better to abandon these

terms. The only question that really matters is the

fol-lowing: is it MF or is it not MF?

Tumor stage MF is often associated with a poor

prog-nosis. However, this and other studies

11,12,14

_clearly

indi-cate that patients with skin tumors without concurrent

extracutaneous disease (stage Ic) still have a

disease-related 5-year survival of approximately 70% to 80%.

Whether patients with enlarged, but histologically

unin-volved, lymph nodes (stage II) have a more unfavorable

prognosis compared with patients without clinically

en-larged lymph nodes is a matter of controversy.

4,11,13

_{In the}

present study, patients with stage II disease had a

signifi-cantly lower survival rate than patients with stage I MF

(P.001). Previous studies

27

_{suggested that T-cell}

recep-tor gene rearrangement analysis is a more accurate and

objective method of diagnosing early lymph node

in-volvement in patients with MF than routine histological

features. However, in prior studies,

28

_{which included}

lymph nodes of 7 of the 18 patients with stage II MF

in-cluded in this study, no clonal T-cell populations were

found in any of the dermatopathic, but noninvolved,

lymph nodes. There is, therefore, no evidence that the

lymph nodes of these patients with stage II MF were

ac-tually involved, which leaves the more unfavorable

prog-nosis of this group unexplained.

Table 5. Actual Disease Progression in 309 Patients With MF After a Median Follow-up of 62 Months*

Stage at Diagnosis Skin Tumors Lymph NodeInvolvement InvolvementVisceral Death Dueto MF Progression† Disease Progression, mo‡Duration Until

Ia (n = 89) 3 (3) 2 (2) 1 (1) 2 (2) 4 (4) 73 (49-96) Ib (n = 135) 28 (21) 19 (14) 5 (4) 13 (10) 33 (24) 45 (8-109) Ic (n = 46) 0 11 (24) 7 (15) 15 (33) 18 (39) 37 (1-242) II (n = 18) 3 (17) 5 (28) 2 (11) 4 (22) 9 (50) 24 (14-51) III (n = 18) 2 (11) 0 3 (17) 11 (61) 11 (61) 32 (8-56) IV (n = 3) 0 0 0 2 (67) 2 (67) 6 (2-9) Total (N = 309) 36 (12) 37 (12) 18 (6) 47 (15) 77 (25) 40 (1-242)

*Data are given as number (percentage) of patients unless otherwise indicated. The clinical stages are explained in the footnote to Table 1. MF indicates mycosis fungoides.

†Total number (percentage) of patients showing disease progression.

‡Data are given as the median (range).

(10)

In the literature, the following prognostic variables

have been described: stage of disease,

3-5,11-14

_age,

2,10,12,13

race,

2

_{response to initial treatment,}

3,10,13

_{and prior}

ma-lignant neoplasm.

2

_{In the present study, stage at}

diagno-sis (ie, the presence of extracutaneous disease and the

type of skin involvement), complete remission after

ini-tial treatment, and the presence of follicular mucinosis

proved independently predictive of disease-specific

sur-vival and disease progression.

In the group of 32 patients with MF-associated

fol-licular mucinosis, disease progression occurred more

often and disease-specific survival rates were

signifi-cantly lower than in the 277 patients without follicular

mucinosis. In the 32 patients with follicular mucinosis,

disease progression was estimated to occur in 89%

within 10 years after diagnosis vs 32% in the 277

pa-tients without follicular mucinosis. The disease-related

survival at 5 and 10 years was 81% and 36%, and the

overall survival 75% and 21%, respectively. A more

de-tailed clinical and histological analysis of a group of 40

patients with MF-associated follicular mucinosis will be

published separately.

Older patients had significantly lower

disease-specific survival rates and higher disease progression rates.

However, older age was associated with more advanced

stages of MF, and it appeared not to be an independent

prognostic factor.

Mycosis fungoides is generally depicted as a

malig-nant disease that slowly evolves through patch, plaque,

and tumor stages, and ultimately may develop into an

extracutaneous and generally fatal disease. Because of the

increased accessibility of medical literature through

In-ternet services, we are confronted more frequently with

patients with newly diagnosed MF who have come to

be-lieve that this sequence of events invariably takes place.

On the other hand, clinical experience suggests that many

patients with MF, in particular those with stage Ia and

perhaps also many with stage Ib disease, may have stable

disease for decades, and that only a proportion of

pa-tients with MF progresses and will develop

extracutane-ous disease. Consistently, the results of this and other

recent studies

10,12,13

_{indicate that the risk of disease}

pro-gression within the first 10 years after diagnosis is about

5% to 10% for patients with stage Ia and between 17%

and 39% for patients with stage Ib disease. In patients

with more advanced stages of MF, the risk of disease

pro-gression was higher and the duration until propro-gression

shorter (Tables 2 and 5). These results confirm the

clini-cal impression that, at least within the first 10 years

af-ter diagnosis, disease progression occurs in only a few

patients. Further studies are warranted to elucidate the

risk factors associated with disease progression within

these early stages of MF.

Accepted for publication October 26, 1999.

We thank P. D. Bezemer, PhD, P. J. Kostense, PhD, and

J. J. Oudejans, MD, for their statistical advice.

Reprints: Rein Willemze, MD, Department of

Derma-tology, B1-Q-93, Leiden University Medical Center, PO

Box 9600, 2300 RC Leiden, the Netherlands (e-mail:

willemze.dermatology@lumc.nl).

REFERENCES

1. Weinstock M, Horm J. Mycosis fungoides in the United States: increasing inci-dence and descriptive epidemiology.JAMA. 1988;260:42-46.

2. Weinstock M, Horm J. Population-based estimate of survival and determinants of prognosis in patients with mycosis fungoides.Cancer. 1988;62:1658-1661. 3. Lamberg S, Green S, Byar D, et al. Status report of 376 mycosis fungoides pa-tients at 4 years: Mycosis Fungoides Cooperative Group.Cancer Treat Rep. 1979; 63:701-707.

4. Hamminga L, Hermans J, Noordijk E, Meijer C, Scheffer E, van Vloten W. Cuta-neous T-cell lymphoma: clinicopathological relationships, therapy and survival in ninety-two patients.Br J Dermatol. 1982;107:145-155.

5. Sausville E, Eddy J, Makuch R, et al. Histopathological staging at initial diagnosis of mycosis fungoides and the Se´zary syndrome: definition of three distinctive prog-nostic groups.Ann Intern Med. 1988;109:372-382.

6. Hoppe R, Wood G, Abel E. Mycosis fungoides and the Se´zary syndrome: pathol-ogy, staging and treatment.Curr Probl Cancer. 1990;14:293-371. 7. Hermann J, Roenigk H, Hurria A, et al. Treatment of mycosis fungoides with

photochemotherapy (PUVA): long-term follow-up.J Am Acad Dermatol. 1995; 33:234-242.

8. Zackheim H. Topical carmustine (BCNU) for patch/plaque mycosis fungoides. Semin Dermatol. 1994;13:202-206.

9. Quiros P, Kacinski B, Wilson L. Extent of skin involvement as a prognostic indi-cator of disease free survival and overall survival of patients with T3 cutaneous T-cell lymphoma treated with total skin electron beam radiation therapy. Can-cer. 1996;77:1912-1917.

10. Kim Y, Jensen R, Watanabe G, Varghese A, Hoppe R. Clinical stage IA (limited patch and plaque) mycosis fungoides.Arch Dermatol. 1996;132:1309-1313. 11. Toro J, Stoll H, Stomper P, Oseroff A. Prognostic factors and evaluation of mycosis

fungoides and Se´zary syndrome.J Am Acad Dermatol. 1997;37:58-67. 12. Vonderheid E, Ekbote S, Kerrigan K, et al. The prognostic significance of delayed

hypersensitivity to dinitrochlorobenzene and mechlorethamine hydrochloride in cutaneous T cell lymphoma.J Invest Dermatol. 1998;110:946-950. 13. Kim Y, Chow S, Varghese A, Hoppe R. Clinical characteristics and long-term

outcome of patients with generalized patch and/or plaque (T2) mycosis fungoi-des.Arch Dermatol. 1999;135:26-32.

14. Zackheim H, 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 Der-matol. 1999;40:418-425.

15. Beljaards R, Meijer C, Scheffer E, et al. Prognostic significance of CD30 (Ki-1/ Ber-H2) expression in primary cutaneous large-cell lymphomas of T-cell origin: a clinico-pathological and histochemical study in 20 patients.Am J Pathol. 1989; 135:1169-1178.

16. Willemze R, Kerl H, Sterry W, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the Eu-ropean Organization for Research and Treatment of Cancer.Blood. 1997;90: 354-371.

17. Nickoloff BJ. Light-microscopic assessment of 100 patients with patch/plaque stage mycosis fungoides.Am J Dermatopathol. 1988;10:469-477. 18. Fuks Z, Bagshaw M, Farber E. Prognostic signs and the management of the

my-cosis fungoides.Cancer. 1973;32:1385-1395.

19. Bunn P, Lamberg S. Report of the Committee on Staging and Classification of Cutaneous T-Cell Lymphomas.Cancer Treat Rep. 1979;63:725-728. 20. Scheffer E, Meijer C, Van Vloten W. Dermatopathic lymphadenopathy and lymph

node involvement in mycosis fungoides.Cancer. 1980;45:137-148. 21. Kaplan E, Meier P. Nonparametric estimation from incomplete observations.

J Am Stat Assoc. 1958;53:475-480.

22. Cox D, Snell E.Analysis of Binary Data. New York, NY: Chapman & Hall; 1989. 23. Beljaards R, Willemze R. The prognosis of patients with lymphomatoid papulosis associated with other types of malignancies.Br J Dermatol. 1992;126:596-602. 24. Basarab T, Fraser-Andrews E, Orchard G, et al. Lymphomatoid papulosis in

as-sociation with mycosis fungoides: a study of 15 cases.Br J Dermatol. 1998;139: 630-638.

25. Wilson L, Cooper D, Goodrich A, et al. Impact of non-CTL dermatologic diagno-sis on cutaneous T-cell lymphoma patients treated with total skin electron beam radiation therapy.Int J Radiat Oncol Biol Phys. 1994;28:829-837. 26. King-Ismael D, Ackerman AB. Guttate parapsoriasis/digitate dermatosis (small plaque

parapsoriasis) is mycosis fungoides.Am J Dermatopathol. 1992;14:518-530. 27. Weiss LM, Hu E, Wood GS, et al. Clonal rearrangements of T-cell receptor genes

in mycosis fungoides and dermatopathic lymphadenopathy.N Engl J Med. 1985; 313:539-544.

28. Bakels V, van Oostveen JW, Geerts ML, et al. Diagnostic and prognostic signifi-cance of clonal T-cell receptor beta gene rearrangements in lymph nodes of pa-tients with mycosis fungoides.J Pathol. 1993;170:249-255.

(11)

(12)

Chapter 3 Follicular mycosis fungoides, a distinct disease entity

with or without associated follicular mucinosis:

a clinicopathologic and follow-up study of 51 patients

(13)

(14)

Follicular Mycosis Fungoides, a Distinct Disease

Entity With or Without Associated Follicular Mucinosis

A Clinicopathologic and Follow-up Study of 51 Patients

Remco van Doorn, MD; Erik Scheffer, MD; Rein Willemze, MD; for the Dutch Cutaneous Lymphoma Group

Objective:

To determine the clinicopathologic

fea-tures and the disease course of patients with follicular

mycosis fungoides (MF).

Design:

A multicenter, 14-year, retrospective cohort

analysis.

Setting:

Dutch Cutaneous Lymphoma Group.

Patients:

Fifty-one patients with the clinicopathologic

features of follicular MF with (n=49) or without (n=2)

associated follicular mucinosis. Follow-up data were

com-pared with those of 158 patients with the classic

epider-motropic type of MF, including 122 patients with

gen-eralized plaque-stage MF (T2 N0 M0) and 36 patients

with tumor-stage MF (T3 N0 M0).

Observations:

Characteristic clinical features not or

rarely observed in classic MF were the preferential

lo-calization of the skin lesions in the head and neck

re-gion (45 of 51 patients), the presence of follicular

pap-ules, alopecia, acneiform lesions, mucinorrhoea, and often

severe pruritus. Characteristic histologic findings were

the presence of perifollicular neoplastic infiltrates with

a variable degree of folliculotropism, but generally no

epi-dermotropism, follicular mucinosis (49 of 51 cases), and

often a considerable admixture of eosinophils and plasma

cells. Response on initial treatment, risk of disease

pro-gression (development of extracutaneous disease and/or

death from lymphoma), and disease-specific and

over-all survival of patients with follicular MF were worse than

in classic MF patients. The actuarial disease-specific

sur-vival was 68% at 5 years and 26% at 10 years.

Conclusions:

Follicular MF shows distinctive

clinico-pathologic features, is more refractory to treatment, and

has a worse prognosis than the classic type of MF; it should

be considered a distinct type of cutaneous T-cell

lym-phoma. Based on these results and those of other

stud-ies, we suggest the term follicular MF for cases with or

without associated follicular mucinosis.

Arch Dermatol. 2002;138:191-198

M

YCOSIS

fungoides (MF)

is the most common

typeofcutaneousT-cell

lymphoma,

character-ized clinically by an

indolent clinical course with the

subse-quent evolution of patches, plaques, and

tumors, and histologically by the

infiltra-tion of the epidermis by medium-sized to

large atypical T cells with cerebriform

nuclei.

1

In the first 10 years after diagnosis,

dis-ease progression, including development

of extracutaneous disease and

disease-related deaths, occurs in only a minority of

patients.

2

_{Apart from this so-called classic}

Alibert-Bazin type of MF, many clinical and

histologic subtypes have been reported,

including hypopigmented, vesicular,

pustular, granulomatous, and other types

of MF. Since these variant types of MF

have the same clinical course and clinical

behavior and require the same

therapeu-tic approach as the classic type of MF, they

are generally not considered separate

entities. In both the EORTC (European

Organization for Research on the

Treat-ment of Cancer)

1

_{classification for}

pri-mary cutaneous lymphomas and in the

WHO (World Health Organization)

clas-sification,

3

_{only pagetoid reticulosis and}

MF-associated follicular mucinosis have

been categorized as separate entities.

Hereinafter, the latter condition will be

referred to as follicular MF, a term also

used in the WHO classification for cases

with or without associated follicular

mucinosis.

Follicular MF has been classified as a

separate entity because it has distinctive

clinical and histologic features, is more

re-fractory to standard treatment, and has a

worse prognosis than classic MF.

How-ever, this observation is particularly based

on clinical experience of members of the

classification committee of the EORTC

Cu-taneous Lymphoma Group and is not

sub-See also pages 182 and 244

STUDY

(15)

stantiated sufficiently in the literature. In fact,

pub-lished reports on follicular MF are relatively scarce,

generally concern case reports or small series of

pa-tients, and have mainly been focused on differentiation

between MF-associated follicular mucinosis and

alope-cia mucinosa, the benign idiopathic form of follicular

mucinosis.

4-9

In a recent study by members of our group

2

_{on 309}

patients with MF, the 32 patients with follicular MF

seemed to have significantly higher disease progression

and mortality rates than the 277 patients without

fol-licular mucinosis. These observations prompted us to

re-view all cases of follicular MF registered at the Dutch

Cu-taneous Lymphoma Group between 1985 and 1998.

RESULTS

CLINICAL CHARACTERISTICS

The main clinical features and relevant follow-up data

have been summarized in

Table 1

. Fifty-one patients,

including 42 male and 9 female, were included in this

study. Four (8%) of 51 patients were younger than 40

years at the time of diagnosis. At the time of diagnosis,

49 patients (96%) had disease confined to the skin,

in-cluding 4 patients with enlarged but histologically

un-involved lymph nodes, whereas 1 patient had

concur-rent lymph node involvement and another, concurconcur-rent

visceral involvement.

At the time of diagnosis, 34 of 51 patients had only

patches, plaques, or (grouped) follicular papules, often

associated with alopecia; 14 had (concurrent) nodules

or tumors; and 3 had erythroderma (

Figure 1

).

Acne-iform lesions, including comedolike lesions and

epider-mal cysts, were a prominent feature in 4 patients.

Mucinorrhea (ie, discharge of mucinous substance from

the follicular orifices) was noted in 3 patients. During

the course of their disease, 2 patients developed a

leo-nine face (

Figure 2

). In 45 of 51 patients, the skin

le-sions were preferentially localized in the head and neck

region at the time of diagnosis. A characteristic finding

in 25 of these 45 patients was the presence of plaques or

tumors on the head or neck, whereas the trunk and

ex-tremities showed only patches or slightly infiltrated

plaques and/or grouped follicular papules (Figure 1A-B).

Infiltrated plaques in the eyebrows with concurrent

alo-pecia were a common finding. Most patients had

mod-erate to severe pruritus.

PATIENTS AND METHODS

Between October 1985 and December 1998, 57 patients with

follicular MF were included in the registry of the Dutch

Cu-taneous Lymphoma Group. Three of the 57 had to be

ex-cluded from the present study, 1 because of incomplete

fol-low-up data and 2 because of lack of representative skin

biopsy specimens. Another 3 patients were excluded

be-cause they had a history of classic epidermotropic MF for 4

to 7 years before they developed skin tumors on the face with

the histologic features of MF-associated follicular

mucino-sis. The final study group consisted of 51 patients. In each

patient the diagnosis had been made by an expert panel of

dermatologists and pathologists at one of the quarterly

meet-ings of the Dutch Cutaneous Lymphoma Group. The main

criteria for diagnosis and for inclusion in the study were the

presence of perifollicular-to-diffuse dermal infiltrates with

variable numbers of atypical T cells with cerebriform

nu-clei infiltrating the follicular epithelium and the presence of

mucinous degeneration of the follicular epithelium, as

con-firmed by Alcian blue staining of the first diagnostic biopsy

specimens (diagnostic specimens).

6,7

_{Forty-nine patients met}

both criteria. Two cases with the same cytoarchitectural

fea-tures in the diagnostic specimen but without associated

fol-licular mucinosis were included as well. The time of

evalu-ation of the first diagnostic specimen was considered the time

of diagnosis.

In all cases diagnostic evaluation at the time of

diag-nosis consisted of a thorough physical examination,

com-plete blood cell count, serum chemistry studies, and skin

specimen evaluation. Lymph node biopsies and thoracic

and abdominal computed tomographic scans were

per-formed only in patients with enlarged peripheral lymph

nodes. Lymph node involvement was assessed using

crite-ria described previously.

10

_{When indicated clinically,}

additional studies to determine visceral involvement were

performed.

In all cases clinical records and follow-up data, which

had been collected yearly, were evaluated. The following

vari-ables were recorded: age; sex; duration of skin lesions

be-fore diagnosis; type of initial therapy; whether there was a

complete remission after initial therapy; the date of disease

progression if applicable; and the date of last contact (or death

if applicable). Because of difficulties in defining skin stage

in patients with follicular MF, disease progression was

de-fined by the development of histologically documented nodal

involvement in patients with previously skin-limited

dis-ease, the development of visceral involvement in patients with

prior skin and/or lymph node involvement, and death due

to lymphoma. In all cases, one or multiple skin biopsy

speci-mens obtained at the time of diagnosis, and in most cases

also obtained during follow-up, were reviewed.

To evaluate differences in clinical behavior between

follicular MF and classic MF, 49 patients with follicular MF

presenting with disease confined to the skin were

com-pared with 158 patients with classic MF included in an

ear-lier study.

2

_{This latter group included 122 patients with}

gen-eralized plaque-stage MF (T2 N0 M0) and 36 patients with

tumor-stage MF (T3 N0 M0) without evidence of

extracu-taneous disease and without associated follicular

mucino-sis at the time of diagnomucino-sis.

Actuarial survival curves were calculated from the date

of diagnosis to the date of last contact (or the date of death)

using the Kaplan-Meier technique. Differences between

sur-vival and disease progression curves were analyzed using

the log-rank test. Univariate analysis of possible

prognos-tic factors was performed using the log-rank test and Cox

proportional hazards regression analysis. Patients lost to

follow-up were considered censored at the time of last

con-tact. Analyses were performed using the SPSS statistical

soft-ware (SPSS Inc, Chicago, Ill).

(16)

HISTOLOGIC FEATURES

A total of 74 representative skin biopsy specimens from these

51 patients were reviewed. These included the 51

diagnos-tic specimens, 8 prediagnosdiagnos-tic specimens obtained 4 to 30

months (median, 12 months) prior to diagnosis, and 15

specimens obtained during follow-up at the time of

re-lapse or disease progression. Characteristically, the

diag-nostic specimens showed perifollicular and

perivascular-to-diffuse dermal infiltrates with variable infiltration of the

follicular epithelium by medium-sized to large atypical T

cells with cerebriform nuclei (

Figure 3

). Pautrier

micro-abscesses appeared in only a minority of specimens.

Infil-tration of the interfollicular epidermis by (atypical) T cells,

as in classic MF, was rare. Only 5 of 51 specimens showed

infiltration of both the epidermis (epidermotropism) and

the follicular epithelium (folliculotropism). Prominent

in-filtration of the eccrine sweat glands was observed in 3

speci-mens. In all but 2 cases, the skin specimens showed

mu-cinous degeneration of the hair follicles, varying from focal

spots of mucin deposition (which had to be searched for

in serial sections) to lakes of mucin (Figure 3B).

The number of atypical T cells infiltrating the

follicu-lar epithelium was generally low and did not correlate with

the amount of mucin deposition. The perifollicular

infil-trates consisted of variable numbers of medium-sized to

large atypical T cells with cerebriform nuclei and blast cells

and admixed small lymphocytes, histiocytes, eosinophils

(which were numerous in 13 of 51 specimens), and plasma

cells, in particular in patients with secondary bacterial

in-fection (Figure 3C). Concurrent patches on the trunk

showed essentially the same histologic features, though the

number of atypical T cells was often less than in the more

infiltrated lesions in the head and neck, which made a

defi-nite diagnosis in these specimens more difficult or even

impossible.

Immunohistochemical analysis demonstrated a

CD3

+

_-CD4

+

_-CD8

−

_{phenotype of the neoplastic T cells in}

all cases studied. Small numbers of scattered CD30

+

_blast

cells were regularly observed, as were small clusters of

ad-mixed B cells. In the initial diagnostic specimens of 7 of

the 51 patients, we found a considerable number of blast

cells (�15%; generally a mixture of CD30

+

_{and CD30}

−

_blast

cells). Six of these 7 patients died of lymphoma 11 to 100

months (median, 40 months) after diagnosis.

In follow-up specimens taken during disease

pro-gression, the dermal infiltrates tended to become more

diffuse, sometimes showed complete effacement of the

follicular structures, and invariably showed increasing

numbers of CD30

−

_{and/or CD30}

+

_{blast cells. In the 8}

pre-diagnostic specimens, the dermal infiltrates were mainly

confined to the perifollicular areas. Although some of these

specimens already contained small numbers of atypical

T cells in the follicular epithelium and in the

perifollicu-lar infiltrates, the size and morphologic characteristics

of the infiltrating T cells did not warrant a definite

diag-nosis of follicular MF.

THERAPY AND FOLLOW-UP

InitialtherapyconsistedofpsoralenplusUV-A(PUVA)treat-ment in 22 patients and total skin electron beam

irradia-tion (TSEBI) in 11 patients (Table 1). Seven patients were

initially treated with local radiotherapy in combination with

other therapies, including PUVA with or without

reti-noids, UV-B, topical mechlorethamine, or topical steroids.

For the remaining patients treatments included topical

ste-roids(3patients),topicalmechlorethamine(1patient),UV-B

(1 patient), PUVA in combination with retinoids (1

pa-tient), prednisone (1 papa-tient), azathioprine in

combina-tion with topical mechlorethamine (1 patient), or

poly-chemotherapy (2 patients). One patient refused treatment.

Only 8 (16%) of 51 patients, each with disease

con-fined to the skin, achieved complete remission on initial

treatment. Six of them had been treated with TSEBI, 1 with

PUVA, and 1 with a combination of PUVA, retinoids, and

local radiotherapy. Two of these 7 patients were still in

com-plete remission after a follow-up of 38 and 192 months,

respectively, and may be considered cured.

Table 1. Clinical Characteristics and Follow-up Data

of 51 Patients With Follicular Mycosis Fungoides*

Characteristic Finding

Age at diagnosis, median (range), y 57 (15-84) Male-female ratio 4.7 (42:9) Duration of skin lesions before diagnosis,

median (range), mo 48 (4-156) Type of skin lesions at diagnosis

Patches/plaques/papules 44 (86)

Nodules/tumors 14 (27)

Cysts/comedones 4 (8)

Erythroderma 3 (6)

Clinical stage at diagnosis

Only skin lesions 45 (88) Enlarged, but uninvolved nodes (DL) 4 (8) Lymph node involvement 1 (2) Visceral involvement 1 (2) Folicular mucinosis Present 49 (96) Absent 2 (4) Initial treatment PUVA 22 (43) TSEBI 11 (22) Radiotherapy + other 7 (14) Other 11 (22)

Complete remission on initial therapy 8 (16) Calculated risk of disease progression†, %

At 5 y 37

At 10 y 66

Current status

Alive without disease 5 (10) Alive with disease 20 (39) Died of other cause 6 (12)

Died of FMF 20 (39) Disease-specific survival, % At 5 y 68 At 10 y 26 Overall survival, % At 5 y 64 At 10 y 14

*Unless otherwise indicated, data are number (percentage) of patients. DL indicates histologic features of dermatopathic lymphadenopathy; PUVA, psoralen plus UV-A therapy; TSEBI, total skin electron beam irradiation; and FMF, follicular mycosis fungoides.

†Disease progression means development of extracutaneous disease and/or death from lymphoma.

(17)

The follow-up period varied between 8 and 239

months (median, 48 months; mean, 58 months).

Devel-opment of lymph node or visceral involvement was

docu-mented in 14 and 7 patients, respectively. Disease

pro-gression defined as the development of extracutaneous

disease or death from lymphoma occurred in 20 (39%)

of 51 patients, and occurred 11 to 168 months (median,

45 months) after diagnosis. The calculated risk of

dis-ease progression during the first 5 years after diagnosis

was 37%; at 10 years, 66%. At the conclusion of the study,

26 patients had died, 20 from lymphoma. The 5- and

10-year disease-specific survival rate was 68% and 26%,

re-spectively. The respective overall survival rates at 5 and

10 years were 64% and 14%. Univariate analysis

dem-onstrated no association between disease-specific

sur-vival and age at diagnosis, sex, duration of skin lesions

before diagnosis, or response to initial treatment.

FOLLICULAR MF VS CLASSIC MF

To evaluate differences in clinical behavior and

progno-sis between follicular MF and classic MF, we compared

A B

C D

E F

Figure 1. Clinical appearances of follicular mycosis fungoides. A, Boggy infiltrates on the cheek and neck; B, concurrent grouped follicular papules on the trunk;

(18)

relevant clinical features of the 49 patients with follicular

MF who had disease confined to the skin with the

fea-tures of 122 patients with generalized plaque-stage MF and

36 patients with tumor-stage MF without evidence of

ex-tracutaneous disease and without associated follicular

mu-cinosis (

Table 2

). Patients with follicular MF showed a

significantly higher male-female ratio and less frequently

achieved complete remission on initial treatment. The

cal-culated risk of disease progression, as defined in this study,

within the first 5 years after diagnosis was 36% for

fol-licular MF vs 12% for classic plaque-stage MF and 24%

for tumor-stage MF. Disease-specific and overall survival

in patients with follicular MF were significantly lower than

in patients with generalized plaque-stage MF, and were

roughly similar to patients with tumor-stage MF without

associated follicular mucinosis (

Figure 4

).

COMMENT

The results of the present study clearly demonstrate that

follicular MF has distinctive clinicopathologic features and

should be considered a distinct disease entity.

Character-istic histologic features include the primary perifollicular

localization of the dermal infiltrates, with variable

infiltra-tion of the follicular epithelium by medium-sized to large

atypical T cells with cerebriform nuclei. In most cases the

epidermis is spared (folliculotropism instead of

epidermo-tropism). Mucinous degeneration of the follicular

epithe-lium occurs in most cases, and a considerable admixture

with eosinophils and plasma cells is frequently present.

Clinical characteristics include the preferential

lo-calization of the skin lesions in the head and neck area (45

of 51 patients), the presence of papules (often grouped),

alopecia, frequent secondary bacterial infection, and, less

commonly, the presence of acneiform lesions and

muci-norrhea. Unlike in classic MF, pruritus is often severe and

may represent a good parameter of disease activity: in

sev-eral patients, a relapse after initial therapy was preceded

by the reappearance of pruritus. In addition, patients with

follicular MF proved generally more refractory to

stan-dard classic MF therapies, showed more frequent disease

progression, and had a less favorable prognosis (Table 2).

This more unfavorable prognosis suggests a true

bio-logical difference in clinical behavior between patients with

follicular MF and patients with the classic epidermotropic

type of MF, which is consistent with the conclusion of a

recent study.

11

_{The similar duration of skin lesions before}

diagnosis in patients with follicular MF and patients with

classic-type MF indicates that the difference in survival

does not simply result from a selection of patients with

A B

C D

Figure 2. Sequential photographs of a 39-year-old man with follicular mycosis fungoides. A, At the time of diagnosis; B, 26 months after diagnosis with a leonine