ARTICLE
Primary cutaneous B-cell lymphomas (PCBCL) account for about 20 to
25 % of all primary cutaneous lymphomas [1]. Recently the Cutaneous
Lymphoma Study Group of the European Organization for Research and Treatment
of Cancer (EORTC) has proposed a specific classification for PCBCL, based
on the assumption that B-cell lymphomas originating in the skin have different
clinico-pathologic, immunohistochemical and molecular features from those
of lymphomas arising at other sites. According to the EORTC classification,
follicle center cell lymphoma (FCCL) is listed among the "indolent"
forms of PCBCL, since "if left untreated, the skin lesions gradually
increase in size over years, but dissemination to extracutaneous sites
is uncommon" [2]. On this basis non-aggressive radiotherapy has been
indicated as the first choice treatment by many studies [3-8] and in particular
during the EORTC Cutaneous Lymphoma Project Group Clinical Meetings held
in Vienna, 1998 and Turin, 1999 [9-10].
After our previous study [11] on 31 cases of FCCL treated with
orthovoltage radiotherapy, our clinical series has been enlarged and the
follow-up prolonged, allowing us to strengthen our experience on this
topic.
Methods and materials
From 1973 to 2000, 146 patients affected by cutaneous B-cell lymphoma
have been treated with radiotherapy at the Department of Photoradiotherapy:
all have been classified or re-classified according to the recent EORTC
lymphoma group classification [2]. The series here reported is composed
of 104 patients diagnosed as FCCL who underwent radiotherapy as first-line
treatment. Cases diagnosed as immunocytoma or marginal cell lymphoma as
well as cases of FCCL previously treated with other therapies have not
been included.
The group consisted of 67 males and 37 females, with a mean
age of 53.7 years (range: 23-86 years) at the beginning of the
treatment.
The diagnosis was formulated after histopathological examination of
the skin lesions, integrated by immunohistochemical analysis and, starting
from 1987, by molecular biology techniques to look for clonality of proliferating
lymphocytes. Staging investigations (complete blood cell count, hepatic
and renal function tests, chest x-ray study, abdominal sonography, bone
marrow biopsy and chest and abdominal CT scan) were performed at the time
of the diagnosis in all patients except for those diagnosed before 1985.
Such patients underwent the lacking investigations during the follow-up
re-staging procedures. No extracutaneous involvement was observed.
At the onset of the disease patients showed either solitary (48 cases)
or multiple (56 cases) plaques or nodular lesions localized on the
head, trunk and limbs (Table
I).
All the patients underwent orthovoltage radiotherapy [12]: forty-nine
cases were treated with contact x-ray therapy (CRT) according to Chaoul,
34 cases with half-deep x-ray therapy (HDRT) and 6 cases with
soft x-ray therapy (SRT). The remaining 15 cases were treated with
a combination of the different techniques on lesions covered by irradiation
fields of different sizes (13 cases with CRT and HDRT, 1 case
with CRT and SRT and 1 case with HDRT, CRT and SRT). The technical
data of radiation techniques are indicated in Table
II. In total, 214 irradiation fields were performed. A margin
of 1 cm of healthy skin around the lesion was included in the irradiation
field. In cases of extensive lesions the irradiation was performed by
means of juxtaposed fields. The total dose ranged from 14 to 35 Gy
(mean 23.55 Gy, median 20 Gy). The fractionation of the dose
was differentiated on the basis of the kind of technique used (Table
II). In the case of SRT the different fractionation (2.5 Gy twice
in a week or 5 Gy once in a week) was due to the intense skin reaction
which occurred in one case, that required the administration of a lower
dose per fraction. Lead rubber shields (equivalent to 4 mm Pb) were
employed to protect the critical organs (thyroid and gonads).
All the data were processed with Excel 5.0 software (Microsoft).
Results
Two out of 104 patients did not present at the first control after
the radiotherapy, so they were lost to follow-up and are not included
in the following analysis. The mean follow-up was 65.08 months (range:
1-288 months). The patients were seen one month after the end of
radiotherapy, then every sixth months for 5 years and then once a
year.
In all cases (102/102), the therapeutic response was a complete remission
in the irradiation field. A relapse of the disease, defined as the recurrence
of the treated lesion or the appearence of new lesions, was observed (Tables
I-III):
locally, within the irradiation field (18 cases)
in the same skin region as the treated lesions, but out of the irradiation
field (61 cases)
in a skin region different from that of the treated lesions (19 cases).
A combination of more than one type of relapse was observed in some
cases (Table III).
Extracutaneous progression, defined as the involvement of lymph nodes
or other tissues different from skin, was observed in 9 cases (8.82 %)
(6 to lymph nodes, 1 to lymph nodes and bone marrow, 1 to
bone, 1 to lymph nodes and bowel). The interval of time free from
relapse ranged from 1 to 136 months (mean: 22.03 months).
Up to now, only 26 cases (25.49 %) have been free from any
kind of relapse.
The skin relapses were treated with new courses of dermatologic radiotherapy,
or topical steroids, or intralesional interferon, or intralesional steroid,
according to their extension and infiltration. In case of extracutaneous
progression, the patients were addressed to hematologists and underwent
polychemotherapy (CHOP schedule) and/or deep radiotherapy (one case with
involvement of mediastinal lymph nodes) or surgery (one case with bowel
involvement). The follow-up data of the patients treated for relapse indicate
44 cases alive without disease, 29 alive with disease, 3 dead
patients (one with disease, but not from it).
The relapse-free rate was 42.78 % after 2 years, 22.82 %
after 5 years and 18.36 % after 10 years (Fig. 1),
while the overall actuarial survival rate was 97.36 % after 5 years
and 94.62 % after 10 years (Fig. 2). These values were
calculated according to the life table method [13].
Out of the 74 patients, who are at present in follow-up, 57 (55.88 %
of all cases) are free of disease. Four patients died: one with disease,
and 3 without disease. Twenty-four patients have been lost to follow-up
(range 1-144 months): at the last available check-up 10 were
free from disease and 14 presented skin relapses of the lymphoma.
No complications or sequelae to radiotherapy were observed, except in
one case where a radiogenic ulcer on the leg occurred 8 years after
the treatment following a traumatic injury. The lesion healed with medical
treatment.
Discussion
The use of radiotherapy in the management of FCCL is well known: the
radiosensitivity of the disease is high and several reports on this topic
have been published in the literature [3-8]. However, our series (104 patients)
is one of the largest, after the one described by Pimpinelli [8] (115 patients),
and our results require a thorough analysis being somehow different from
those reported by others. In fact, after a complete remission obtained
in the totality of the cases treated, we observed a high rate of recurrence:
the relapse-free rate was 42.78 % after 2 years, 22.82 %
after 5 years and 18.36 % after 10 years from the end of
the course of radiotherapy. Rijlaarsdam [6] reports a disease-free survival
of 85 % after 2 years, Kirova [7] has obtained a disease-free
survival of 91 % after 1 year and of 75 % at 5 years,
and Pimpinelli [8] refers a relapse rate of about 30 % without specifying
a time interval. On the other hand, our data on the overall actuarial
survival rate are superimposable to or better than those of the literature:
in fact the survival rate after 5 years was 97.36 % (Pimpinelli
[8] 98.3 %, Rijlaarsdam [6] 89 % and Kirova [7] 73 %).
A comparison between patients who did not present any relapse and those
with recurrences did not show significative differences, except that in
the first group the percentage of cases presenting a single localization
of the disease was higher than in the second group (65 % versus 38 %).
As to relapses and their localization, we have found that most recurrences
concerned cases with multiple sites of involvement and cases localized
on the lower limbs (a small number in our series) and trunk (Table
I). The mean dose of ionizing radiations administered in the cases
that have relapsed was similar to the total mean dose of the whole series
(24.26 versus 23.55 Gy). Such data should indicate the influence
of the biological behaviour of the lymphoma ab initio (multiple
lesions and site of the disease) [14, 15], while neither doses nor treatment
techniques of dermatologic radiotherapy appear determinant in the final
outcome. To contradict this statement a selected series of patients affected
by "Multifocal primary cutaneous B-cell lymphoma" was recently
reported in the literature [16]. It regarded 5 patients, out of 16 with
the same diagnosis, who were treated with radiotherapy: they experienced
a complete remission with a 5-year overall survival of 100 %. In
these cases a major role has probably been played by the energy employed
(4-10 MeV electrons) and the total dose (40 Gy) administered,
even if the number of patients is rather low to draw definite conclusions.
The choice of the size of the irradiation fields reported in our preliminary
study [11] was criticized [6]: a margin of 0.5-1 cm in apparently
healthy skin was not considered safe and one of 2 cm was recommended.
However, when looking at the site of the skin relapses in our series (Table III),
it is evident that the relapses occurred inside or marginally to an irradiation
field only 18 times (23.68 %), while most of them were observed
in the same skin region of the first site of radiotherapy (61 times = 80.26 %),
but outside the irradiation field. On the basis of this observation, the
irradiation field should include the entire skin region interested by
the cutaneous lymphoma. However, we think that, considering the indolent
course of the disease and the high survival rate, such a choice is not
justified.
So far orthovoltage radiotherapy, as first-line treatment, has been
curative in 26 cases (25.49 %), in our series. The seventy-six
cases with any kind of relapse were treated: forty-four of them are now
free from disease (67.89 %) and 29 (38.15 %) show limited skin
involvement. On the whole, combining the results of radiotherapy of primary
lesions and those of salvage therapy of relapses, 55.88 % of patients
are now alive and free from disease.
On the basis of these rather favourable data
some conclusions can be drawn:
- dermatologic radiotherapy is a good therapeutic approach in the management
of primary FCCL, as it leads to a complete and lasting remission in one
quarter of the cases, especially when skin lesions are limited in number
and do not involve different skin regions
- dermatologic radiotherapy may be proposed in the treatment of new
cutaneous presentations of the lymphoma, since in many cases a second
course of radiotherapic treatment can control the disease
- dermatologic radiotherapy may be followed by other types of treatment,
when the disease is relapsing with multiple skin localizations or progressing
to involve other tissues
- dermatologic radiotherapy does not affect the quality of life of the
patients. The fractionation of the dose and the relatively low total doses
administered to skin prevent the onset of sequelae and complications (only
one case of radiogenic ulcer in our series).
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