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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1150-1159
Transformation of Mycosis Fungoides/Sezary Syndrome: Clinical
Characteristics and Prognosis
By
Eleni Diamandidou,
Maria Colome-Grimmer,
Luis Fayad,
Madeleine Duvic, and
Razelle Kurzrock
From the Department of Bioimmunotherapy, Pathology, and Medical
Specialties, University of Texas M.D. Anderson Cancer Center, Houston,
TX.
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ABSTRACT |
The occurrence of large cell transformation has been
well documented in a subgroup of patients with mycosis fungoides/Sezary syndrome (MF/SS). However, because of the rarity of MF/SS, little is
known about the influence of clinicopathologic features in predicting
large cell transformation and about outcome in the transformed cases.
We evaluated all patients with MF/SS who were registered in our clinic
during the study period and for whom pathologic slides for review were
available or could be obtained. Disease was classified as transformed
if biopsy showed large cells ( 4 times the size of a small
lymphocyte) in more than 25% of the infiltrate or if they formed
microscopic nodules. Twenty-six patients with transformation were
identified from a total of 115 evaluable cases with a diagnosis of
MF/SS. The actuarial cumulative probability of transformation reached
39% in 12 years. The median time from diagnosis of MF/SS to
transformation was 12 months (range, 0 to 128 months). Thirty-one
percent of all patients with stage IIB-IV disease at presentation
eventually transformed versus 14% of those with stage I-IIA (P
= .03), with transformation being especially common in patients with
tumors (T3), 46% of whom transformed. Combining elevated  2
microglobulin and lactic dehydrogenase (neither elevated v one
or both elevated) was also predictive for transformation (P = .009). The median survival from initial diagnosis of MF/SS for the
transformed patients was 37 months versus 163 months for the
untransformed group (P = .0029). The median survival from transformation was 19.4 months (range, 2+ to 138 months). The following characteristics were associated with an inferior survival in
transformed patients: (1) early transformation (<2 years from the
diagnosis v 2 years; P = .011) and (2) advanced
stage (IIB-IV v I-IIA; 2-year survival, 23% v 86%;
P = .0035). We conclude that MF/SS patients with stages
IIB-IV disease and, in particular, those with tumors have a high
incidence of large-cell transformation. Patients with transformation
have a relatively poor survival, especially if transformation occurs
early (within 2 years) in the course of disease or if they are staged
as IIB or higher.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
MYCOSIS FUNGOIDES/Sezary syndrome (MF/SS)
is characterized pathologically by epidermotropic infiltrates of clonal
malignant T lymphocytes with cerebriform nuclei.1-4
Although the skin is always involved, disease may occur in
extracutaneous sites such as peripheral blood, lymph nodes, or
viscera.1-4 The clinical course of MF/SS is usually
indolent.5 However, occasionally individuals with MF/SS
develop a morphologic change (transformation) from small- to
intermediate-sized cerebriform cells to a large cell variant, a
condition that may be difficult to differentiate pathologically from
certain other lymphoproliferative disorders such as lymphomatoid
papulosis and Ki-1-positive anaplastic large-cell lymphoma.6-13 The presence of large cells exceeding 25% of
the total lymphoid infiltrate has been used to define large-cell
transformation.11 The incidence of such transformation has
been reported to range between 8% and 55%.7,11-13
Molecular mechanisms responsible for large-cell transformation have not
yet been elucidated. However, immunologic and molecular evidence based
on T-cell receptor analysis indicates that transformed MF/SS represents
evolution of the original malignant clone.14,15
Because of the rarity of MF/SS there are few studies addressing the
value of specific characteristics for predicting which MF/SS patients
will later undergo large-cell transformation. Therefore, to determine
these characteristics as well as the clinical implications and outcome
of large-cell transformation in MF/SS, we reviewed the course of 115 patients with MF/SS.
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PATIENTS AND MATERIALS |
We evaluated all patients with MF/SS who were registered in our clinic
between June 1975 and September 1995 and for whom pathologic slides for
review were available or could be obtained. Patients had a clinical
diagnosis compatible with MF/SS. A pathologic diagnosis of MF/SS was
confirmed by our pathologist (M.C.-G.) according to
criteria described previously.1 In each case, all
pathological slides obtained from referral and through the patients'
entire course were reviewed to determine if evidence existed for
morphologic transformation.
Clinical evaluation.
Twenty-six patients with transformation were identified from a total of
115 evaluable cases of confirmed MF/SS seen at the Mycosis Fungoides
Clinic at M.D. Anderson Cancer Center during the study period. (A total
of 131 patients were seen, but slides were not available for review on
16 of these individuals.) For classification and staging, patients
received a complete physical examination, complete blood cell count
with examination of the peripheral smear for Sezary/lymphoma cells,
serology for human T-cell lymphotropic virus (HTLV-1) and human
immunodeficiency virus (HIV), renal and liver function tests, lactic
dehydrogenase (LDH), 2 microglobulin (2M), chest roentgenogram
(CXR), and skin biopsy. (Patients with elevated serum creatinine that
could account for an elevated serum 2M level were not
counted.) Patients with clinically significant adenopathy had their
nodes evaluated by fine needle aspiration or lymph node biopsy. When
indicated clinically, patients had an extensive staging evaluation,
including bone marrow aspirate and biopsy, and appropriate radiologic
studies to determine visceral involvement.
After the initial evaluation, staging criteria were used according to
the Mycosis Fungoides Cooperative Group (MFCG).16 The
extent of the skin involvement is referred to as the clinical T
category: T1, limited patch/plaques less than 10% of total skin surface; T2, generalized patch/plaques 10% of the total skin surface; T3, tumors; and T4, generalized erythroderma. Lymph nodes were
evaluated by physical exam, and biopsy or fine needle aspirate was
performed if nodes were enlarged. Adenopathy was considered present if
the lymph nodes were palpable and abnormally enlarged (N1). N2 refers
to clinically negative, histologically positive nodes. N3 refers to
adenopathy with pathological involvement. Patients with Sezary syndrome
(SS) were defined as those with erythroderma (T4, stage III) and
circulating Sezary cells (lymphoma cells) 5%. Finding lymphoma cells
in the peripheral blood did not alter the stage of the disease in
accordance with the MFCG staging criteria. Stage I patients had plaque
disease (<10% involvement of the skin = IA; 10% involvement of
the skin = IB); stage II patients had clinical adenopathy (IIA)
and/or tumors (IIB); stage III patients had erythroderma
without (IIIA) or with (IIIB) clinical adenopathy; and stage IV
patients had pathological evidence of lymph node (IVA) or visceral
involvement (IVB).16
Patients had repeat skin biopsies performed at the time of clinical
relapse after treatment. In addition, if adenopathy, tumors, or
visceral disease developed or were suspected during the course of
follow-up, a fine-needle aspiration or biopsy was performed.
Histopathologic and immunologic analysis.
In accordance with previously defined criteria, cases of MF/SS were
classified as having large-cell transformation if at least one biopsy
showed large cells exceeding 25% of the infiltrate throughout or if
they formed microscopic nodules.11,12 A large cell was
defined as a cell that was 4 times or more the size of a small
lymphocyte.17 The infiltrate was classified as diffuse, lichenoid, or patchy, and the thickness of the infiltrate was measured.
Lichenoid indicated a band-like infiltrate of mononuclear cells in the
upper dermis in close proximity to the epidermis; diffuse indicated an
interstitial/perivascular/periadnexal mononuclear cell infiltrate
throughout the dermis; and patchy indicated a predominantly
perivascular and/or periadnexal mononuclear cell infiltrate
throughout the dermis.18
The thickness of the infiltrate was measured from the granular cell
layer of the epidermis to the bottom of the infiltrate using a
micrometer if the measurement was less than 1 mm or using a ruler if
greater than 1 mm. The entire thickness of the infiltrate was measured
in the cases with a diffuse pattern. Only the thickness of the
lichenoid component was measured in the cases with a lichenoid infiltrate. The small foci of lymphocytes around the vessels
and/or adnexa in the deep dermis present in some of the
lichenoid cases were excluded from the measurement of the thickness. In
the cases with a patchy infiltrate, only the upper clearly denser
pattern of the infiltrate was included in the measurement of the
thickness. The small foci of lymphocytes around vessels and adnexa in
the deep dermis were excluded from the measurement of the thickness. The thickness of the infiltrate was not measured in 2 cases because the
initial transformation was in the liver and lymph node, respectively.
Immunohistochemical studies were performed on fresh frozen tissue
sections in 22 of the 26 cases using the avidin-biotin-peroxidase complex method as previously described.19 We used
anti-T-cell antibodies to T-cell-associated antigens [CD2, CD3, CD4,
CD5, CD7, CD8, UCHL-1 (CD45RO), and CD43], B-cell-associated antigens (CD19, CD20, and CD22), and antibodies directed against CD25
(interleukin-2 [IL-2] receptor) and CD30 (Ki-1).
Data analysis.
Statistical analyses were performed using Statistica, software version
5.0 for Microsoft windows (StatSoft, Tulsa, OK). The association of
transformation with other characteristics at referral was assessed by
 2 or Fisher exact test as appropriate.20
Survival was calculated from the date of diagnosis to the date of death
or last follow-up evaluation. Survival after transformation was
calculated from the time of the first biopsy that established
transformation to the date of the death or last follow-up evaluation.
Survival and actuarial curves were estimated by the method of Kaplan
and Meier.20 Differences between survival curves were
tested by the log-rank test21 and generalized Wilcoxon test
of Gehan,22 as appropriate . All causes of death were
included in the survival analysis.
The following characteristics were evaluated for prognostic value: age,
sex, stage, peripheral blood and bone marrow involvement, transformation, type of skin infiltration at transformation (lichenoid, diffuse, patchy), thickness of the infiltrate at transformation, site
of transformation (skin, lymph node), response to initial and
subsequent treatments before transformation, high LDH, and high 2M.
High LDH was defined as 10% above the upper limit of the normal
range (225 U/L before November 1988 and 618 U/L after November 1988).
For 2M, the cut-off value for normal range was 2 mg/L (>2
v  2; Pharmacia 2M microradioimmunoassay; Pharmacia Diagnostic, Uppsala Sweden).
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RESULTS |
One-hundred fifteen patients with MF/SS were seen at the M.D. Anderson
Cancer Center during the study period and had pathologic slides
available for review. One-hundred thirteen had been followed for 2
years. Twenty-six of the 115 patients (23%) demonstrated morphologic
transformation to a large-cell variant at some point during their
disease. These patients included 13 women and 13 men. Their median age
at transformation was 65 years (range, 29 to 80 years). Serology for
HTLV-1 and HIV testing was negative in all cases. The actuarial
(cumulative probability) of transformation was 21% (95% confidence
interval [CI], 13% to 29%) at 4 years, 32% (95% CI,
20% to 44%) at 8 years, and 39% (95% CI, 23% to 55%) at 12 years
(Fig 1).
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| Fig 1.
Cumulative probability of transformation in 115 patients
with MF/SS. A Kaplan-Meier curve shows the number of patients who transformed ( ) as a function of time, beginning with the diagnosis of MF/SS. Tick marks represent last follow-up of patients without transformation.
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The majority of patients (N =18) had transformation of MF/SS within the
first 2 years from diagnosis (Fig 1). Nine patients were diagnosed with
transformed MF/SS at (or within 1 month) of initial presentation
(Table 1). However, these patients had a long history of dermatitis compatible with clinical MF that preceded the pathological diagnosis of transformed MF/SS.
With regard to site of transformation of MF/SS, it presented initially
in skin in 24 cases, in lymph nodes in 3 cases (in 2 of these cases,
transformation presented in both skin and lymph nodes), and in liver in
1 case (Table 1).
Histopathologic analysis.
Before transformation, the cells retain the hyperchromatic, cerebriform
nuclei of malignant T cells, whereas after transformation, the
malignant cells have larger, more vesicular nuclei
(Fig 2A and B). Histologic evaluation of
the skin lesions in transformed cases demonstrated that most of them (N = 15) had a diffuse lymphoid infiltrate. Five cases had a lichenoid and
4 had a patchy lymphoid infiltrate in the skin. The median thickness of
the infiltrate was 2.15 mm (range, 0.5 to 10 mm; 95% CI, 1.875 to
4.174 mm). Patients with tumor stage (T3) disease had thicker lymphoid
infiltrates compared with patients with T2 or T4 stage disease, as well
as an increased incidence of diffuse pattern of infiltration (P = .0123 and P = .03, respectively).
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| Fig 2.
(A) MF before transformation. The Pautrier's
microabscesses show intermediate-sized lymphocytes with hyperchromatic
cerebriform nuclei. (B) MF after transformation. There is a micronodule
in the papillary dermis composed of large lymphoid cells with clear vesicular nuclei and prominent nucleoli characteristic of large-cell transformation.
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Immunophenotypic analysis.
Immunohistochemical results were reported in 22 of the 26 cases of
transformed MF/SS. In all cases, transformed large cells were typed as
being of T-cell origin. All cases except 1 (case no. 24) examined for
CD4 (T-helper cell) were positive for this marker. This case was
CD4 and CD8. Two cases were
CD8+ (T-suppressor cell marker) as well as CD4+
(cases no. 1 and 11). Immunologic typing was performed on
pretransformation and posttransformation biopsies in 4 cases and showed
no differences. At the time of transformation, CD25 (IL-2 receptor)
marker was weakly positive in all of the 4 cases in which it was
tested. CD30 (Ki-1) expression was present in 7 cases and weakly
expressed in 1 additional case of a total of 15 cases analyzed for this marker.
Correlation between characteristics at referral and eventual
transformation.
There was no difference in age group or in sex distribution between
patients with and without eventual transformation
(Table 2). There was also no statistical
difference between the incidence of peripheral blood (5% of
Sezary/lymphoma cells) or lymph node involvement in patients with and
without eventual transformation.
Neither initial 2M nor LDH was significantly higher in the patients
with eventual transformation. However, when both these variables were
examined together (both normal v one or both elevated), the
number of patients who eventually transformed was significantly elevated in the latter group (P = .009).
Patients with eventual transformation were more likely to have stage
IIB-IV disease at referral than stages I-IIA (P = .03; Table
2). Transformation was not seen in patients with T1 disease. Thirteen
of 28 tumor stage (T3) patients (46%) underwent transformation (Table
2).
Outcome of transformed versus nontransformed patients.
One-hundred twelve of the total of 115 MF/SS patients have been
observed for at least 2 years. The median time from the initial diagnosis of MF/SS to the documentation of large-cell transformation was 12 months (range, 0 to 128 months; Table 1). The median
follow-up time of surviving patients was 55 months (from the time of
diagnosis) for the transformed group. Of the 89 patients without
transformation, 23 (26%) died during the follow-up period as compared
with 16 (62%) of the 26 patients with transformation. The median
survival from initial diagnosis of MF/SS for patients with
transformation was 37 months; the median survival from diagnosis for
the group that have not transformed was 163 months (P = .0029;
Fig 3). The percentage of patients alive at
4 years from diagnosis was 45% (95% CI, 24% to 66%) in the patients
who eventually transformed versus 73% (95% CI, 62% to 84%) in
patients who have not transformed (P = .01).
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| Fig 3.
Survival (from diagnosis) of MF/SS patients with and
without eventual transformation. Data were analyzed by the method of Kaplan-Meier. A log-rank P value was determined. Tick marks
indicate points at which there are 1 or more patients who were still
alive at the time of the analysis. () Patients who have died.
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Half of all the transformed patients had tumor stage (T3) disease and
46% of all tumor stage patients eventually underwent transformation.
The median survival time (from diagnosis) in transformed (N = 13)
versus untransformed (N = 15) tumor stage (T3) patients was 24.5 months
versus 35 months (P = .61). Similarly, the median survival time from diagnosis in stage IIB patients who eventually transformed did not differ from that of those who did not transform (P = .73). The median survival time from diagnosis in
transformed stage III and IV patients was 24.4 months (95% CI, 0 to 44 months); the median survival time has not been reached in the
untransformed stage III-IV patients at a median follow-up time for
surviving patients of 44 months (P = .13).
Prognostic variables within the tranformed group of patients.
The median survival from transformation was 19.4 months (range, 2+ to
138 months; Table 3 and
Fig 4). The patients who transformed within
the first 2 years after diagnosis (N = 18) had a median survival of
23.5 months; the median survival has not been reached in those with
late (2 years) transformation and 57% of this group are alive at 81 months (95% CI, 20% to 94%; P = .011). The stage of skin
disease (T stage) at the time of pathologically confirmed transformed
MF/SS was also an important prognostic indicator for survival. The
actuarial survival from diagnosis of patients with generalized (T2)
plaque disease was 85% at 2 years, compared with only 23% for
patients with tumor stage (T3) disease and 25% for patients with
erythroderma (T4), a difference that is statistically significant
(P = .0182; Table 4 and
Fig 5).
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| Fig 4.
Overall survival from transformation in MF/SS patients.
Data were analyzed by the method of Kaplan-Meier. Tick marks indicate points at which there are 1 or more patients who were still alive at
the time of the analysis. () Patients who have died.
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Table 4.
Survival (From Transformation) According to Prognostic
Variables in 26 Patients With Transformed MF/SS (Univariate
Analysis)
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| Fig 5.
Survival from transformation in MF/SS according to
clinical T category at transformation (Kaplan-Meier). T2, more than
10% of skin surface involved by plaque (8 patients); T3, cutaneous tumors (13 patients); T4, erythroderma (5 patients). There were no
patients with clinical T1 category. A P value (shown)
was determined by the Gehan-Wilcoxon test. Tick marks indicate points
at which there are 1 or more patients who are still alive at the time
of the analysis. () Patients who have died.
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Comparing survival from transformation in patients staged as I-II
versus III-IV showed no difference (P = .34; Table 4). However,
when patients with histopathologically proven stage IA, IB, and IIA
disease were combined in one group, they had a 2-year actuarial
survival of 86% (95% CI, 60% to 100%) from transformation, whereas
patients with stage IIB disease had a median survival of only 10 months, with only 30% of them alive at 2 years (95% CI, 1% to 59%),
and stage IV patients had a median survival of 15 months from
transformation (P = .04; Table 4). When we combined stages
IIB-IV, the survival curve remained similar to that of stage IV
patients alone (14.5 months median, with 23% of stage IIB-IV patients
alive at 2 years). The overall survival difference between these two
groups (I-IIA v IIB-IV) was statistically significant (P = .0035; Table 4 and Fig 6).
These results indicate that transformed stage IIB patients did as
poorly or worse than transformed stage IV patients but that transformed
stage I-IIA patients did much better.
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| Fig 6.
Survival from transformation in MF/SS patients according
to Mycosis Fungoides Cooperative Group clinical stage at transformation (Kaplan-Meier). Tick marks indicate points at which there are 1 or more
patients who are still alive. () Patients who have died. A log rank
P value is shown. N = 7 for stages I-IIA; N = 19 for stages
IIB-IV.
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Advanced age (60 years old) and the presence of elevated LDH
and/or 2M at the time of transformation was not associated with an inferior survival in the transformed MF/SS patients (Table 4).
Differences in the depth of invasion (thickness of infiltrate; >2.15
v 2.15 mm) or in the histologic distribution of the lymphoid infiltrate (diffuse [15] v patchy [4] or lichenoid [5])
also did not influence the prognosis in the transformed patients
(P = .15 and P = .17, respectively; Table
4).
Treatment of patients with tranformation.
Sixteen patients (62%) received therapy before transformation. The
treatments were diverse, but most commonly included a combination of
systemic (usually interferon, retinoids, and/or chemotherapy) and topical (usually nitrogen mustard, PUVA, or total body
electron beam) treatment, with only 4 patients receiving only topical
treatment. Type of response to previous treatment (complete remission
[CR] versus less than CR) failed to show any influence
on survival after transformation (P = .7). The median survival
from transformation in patients who had prior chemotherapy (N = 8) was
13 months versus 24 months for those without prior systemic
chemotherapy (N = 18; P = .068; Table 3).
Similarly, a wide variety of treatments were used after transformation.
Although the response to the first treatment after the transformation
(CR = 5, other = 21) was associated with a trend towards a better
survival, this did not reach statistical significance (P = .078), perhaps because of the small number of patients. Only 5 patients
achieved a CR after transformation. Among the patients who attained a
CR, 3 had early stage I-IIA disease and 2 had IIB (tumor stage T3)
disease. All those who achieved a CR were treated with a combined
modality approach: interferon- + cis-retinoid acid, followed by
total body electron beam (TBEB), followed by interferon- and topical
nitrogen mustard maintenance in stage I-IIA; multiagent chemotherapy
(cyclophosphamide, methotrexate, etoposide, and dexamethasone [CMED]
alternating with doxorubicin, bleomycin, and vinblastine [ABV]) was
added to the above in stage IIB-IV patients.23 None of
these patients had prior systemic treatment. In addition, a CR was
achieved with CMED (N = 2) and with DCF (N = 1) in some
patients failing to respond to initial therapy. Overall, CMED was the
most common treatment used. Of a total of 12 patients who received it,
either by itself or as part of a combined modality approach
administered immediately after transformation or as salvage, 8 (66%)
attained a CR or partial remission (PR). The median
duration of response in these 8 patients was 6 months (range, 1+ to 42+
months).
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DISCUSSION |
Morphologic transformation has been seen in various hematopoietic
malignancies and is often associated with a more aggressive clinical
course and shorter survival.6 Over the last few years, several investigators have recognized a large-cell variant of MF/SS.6-8,11-13 Transformed MF/SS may be difficult to
differentiate from Ki-1 anaplastic large-cell lymphoma and lymphomatoid
papulosis, because all can be CD30+ and display anaplastic
large cells.9,10 Distinguishing features may be the
presence of small, intermediate, and large atypical lymphocytes in
addition to the large anaplastic cells in transformed MF/SS11 and pertinent clinical features such as spontaneous
regression of disease in lymphomatoid papulosis9 or a
history of extensive skin plaques in MF/SS.4 Molecular
studies have demonstrated that the large-cell infiltrate in transformed
MF/SS represents evolution from the original clone.14,15
Because of the uncommon nature of MF/SS, the exact incidence of
transformed MF/SS is difficult to estimate from the literature. Ranges
of 8% to 55% have been reported.7,11-13 In our study of
115 patients, 26 (23%) showed transformation, and the 4-, 8-, and
12-year cumulative probabilities of transformation were 21%, 32%, and
39%, respectively (Fig 1). However, the relatively high
actuarial probability of transformation could reflect referral bias to
a tertiary care institute. The wide range of reported frequencies for
transformation of MF/SS may be due, at least in part, to different
definitions of transformation, and/or to criteria for patient
selection. Dmitrovsky et al7 reported an 8% incidence of
transformation in their patients, but they defined transformation as
the presence of more than 50% large cells. Cerroni et al12
used the criteria for large cell transformation defined by Salhany et
al11 (the presence of large cells exceeding 25% of the
lymphoid infiltrate throughout or the formation of microscopic nodules
by the large cells), but included only advanced tumor stage disease in
their selected population. They reported an incidence of transformation
approaching 55%.12 In our study, we included all stages of
MF/SS and used a definition similar to that given by Salhany et
al,11 and the overall incidence of transformation was 23%
in our study and 18% in the study by Salhany et al.11 If
we included only tumor stage disease, the incidence of transformation
would be 46%, a figure similar to that reported by Cerroni et
al12 and Vonderheid et al24 (55% and 52%,
respectively).
Clinical features at diagnosis of MF/SS, such as age, sex, and lymph
node, peripheral blood, or bone marrow involvement, were not associated
with a statistically significant increased risk for subsequent
transformation (Table 2). However, although elevated LDH and 2M as
individual factors did not predict for transformation, combining these
two factors did (Table 2). In addition, advanced disease (especially
tumor stage) was strongly associated with transformation. Indeed, half
of the patients with transformation had tumor stage (T3) disease and
46% of all tumor stage patients eventually transformed.
Transformation is generally considered an event occuring late in the
course of a malignancy. However, in transformed MF/SS series, the
median time from diagnosis to transformation is usually less than 2 years, with ranges from 16 months13 to 21.5 months.7 In our current study, the median time from
diagnosis to transformation was 12 months (range, 0 to 128 months).
Occasionally, transformation to a large cell variant can occur at the
time of the diagnosis. In a study by Greer et al13 of 113 patients, 9 patients had transformation at diagnosis (7.9%). This is
very similar to the 9 of 115 patients (7.8%) in our study who had
transformed at diagnosis.
Transformation in MF/SS to a large-cell variant is associated with a
change in the clinical aggressiveness of the malignancy; survival is
often measured in months.7,11-13,24 Indeed, some investigators have suggested that transformed MF/SS may represent an
additional stage of the disease (accelerated form).25 The median survival from transformation has been reported to be as low as 2 months in the study by Dmitrovsky et al7 and 12 months in
the studies by Greer et al13 and Salhany et
al.11 In our current report, the median survival from
transformation was 19.4 months and the 2-year survival was 40% (95%
CI, 20% to 60%; Fig 4).
Despite the relatively small numbers of individuals with
transformation, several features with important prognostic
ramifications emerged. Factors associated with a poor outcome in our
patients were transformation within 2 years after diagnosis (P = .011) and more advanced disease at transformation (stages IIB-IV
v I-IIA; P = .0035). Indeed, transformed patients with
tumor stage (T3) disease had a very poor median survival of 11.5 months
from transformation, with only 23% of them alive at 2 years (Fig 5).
Outcome in these patients was comparable with that of patients with
erythroderma (T4; median survival, 17 months, with 25% of patients
alive at 2 years). Patients with stage T2 plaque disease did much
better; median survival was not reached at a median follow-up of 29 months and 85% were alive at 2 years after transformation (P = .018). Similarly, when we did the analysis of survival according to
stage at transformation, patients with IIB disease had a median
survival of only 10 months from transformation (with 30% of these
patients alive at 2 years); patients with stages III and IV disease had a median survival of 16.5 months (P = .87). Therefore,
transformed patients with stage IIB disease do at least as poorly as
stage III-IV patients. In contrast, the median survival of stage I-IIA transformed patients was not reached and the 2-year survival was 86%
(P = .04; Table 4 and Fig 6). Extracutaneous sites of
transformation have previously been shown to confer a poor prognosis
when compared with transformation confined to the
skin.7,8,11,13 However, in our study, the vast majority of
patients transformed within the skin.
The median survival from diagnosis was 37 months in our patients who
eventually transformed, whereas the median survival in the group who
have not transformed was 163 months (P = .0029). Similar
differences have been reported by Greer et al13 (27 months
for the transformed group compared with 53 months for the nontransformed group).11 A question that arises is whether
the poor median survival of MF/SS patients who transformed is due to
transformation or to the fact that transformation generally takes place
in patients with advanced disease. Within individual stages, survival
was consistently lower in our patients who eventually underwent
transformation versus those who did not. However, these differences
were not statistically significant, perhaps because of the small number
of individuals in each subgroup. Therefore, evaluation of a larger
cohort will probably be needed to address this question.
Immunologic analysis demonstrated expression of T-cell markers in all
transformed cases tested. All cases but 1 retained a T-helper
phenotype. The 1 exception was CD4 and
CD8. Two of the cases had both a CD4 and a CD8
phenotype. Similar patterns of aberrant T subtypes have been seen by
other investigators.11,13 Association of more aggressive
behavior with the expression of activation markers [CD25 and
Ki-1(CD30)] developing after the diagnosis in MF/SS patients has been
suggested.26,27 In our series, CD25 was tested in only 4 cases. CD30 was positive in 7 of the 15 cases tested, and the median
survival for these patients was 21 months.
In patients with transformation of low-grade follicular lymphoma, Yuen
et al28 have demonstrated that long-term survival can be
achieved in individuals with limited disease and/or no prior
chemotherapy. Patients were treated with radiotherapy alone (generally
in limited disease) or with combination chemotherapy. In MF/SS, Kaye et
al29 have shown that aggressive combined therapy (radiation
and adriamycin-based chemotherapy) achieves a higher response rate than
does conservative topical therapy, but it has no impact in survival.
However, the investigators did not specifically address patients with
transformation in their report. In our study, diverse treatments were
also used, precluding a definitive analysis of impact. However, CRs
were for the most part restricted to patients who received multimodal
therapy: interferon and cis-retinoic acid, TBEB, and a multiagent
chemotherapy regimen including methotrexate.
In summary, of our group of 115 patients with MF/SS, 23% underwent
transformation. The cumulative probability of transformation was 39%
at 12 years. Advanced disease (stage IIB and higher) and especially the
presence of tumors as well as elevation of both LDH and 2M were
associated with an increased incidence of transformation. Outcome was
poor in transformed patients if transformation took place within 2 years from diagnosis or if they had advanced stage at presentation. The
median overall survival from transformation was 19.4 months, and
transformed patients with tumors had a median survival of less than 1 year. Considering the poor outlook of these patients, a more systematic
approach to managing individuals with transformed MF/SS appears
warranted.
| |
FOOTNOTES |
Submitted December 15, 1997;
accepted April 1, 1998.
Address reprint requests to Razelle Kurzrock, MD, Department of
Bioimmunotherapy, Box 302, 1515 Holcombe Blvd, University of Texas,
M.D. Anderson Cancer Center, Houston, TX 77030.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract