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cutaneous lymphoma definition
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Diagnostic and Therapeutic Standards in Dermatological Oncology:
Cutaneous Lymphomas
Reinhard Dummer
1. General Information
1.1 Definition
1.2 Classification
2. T-Cell Lymphomas of the Skin
2.1 Mycosis Fungoides
2.2 Sézary's Syndrome
2.3 CD 30+ Large Peripheral T-Cell Lymphomas
3. B-Cell Lymphomas of the Skin
4. Diagnosis
4.1 Biopsy/Histology
4.2 Immunodiagnostic Studies
5. TNM-Stages of the Cutaneous Lymphomas of the Skin
6. Therapy
6.1 Surgical Therapy
6.2 Phototherapy
6.3 Immunotherapy
6.4 Chemotherapy
6.5 Radiotherapy
7. Follow-Up Evaluation
8. References
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1. General Information
1.1. Definition
Cutaneous lymphoma are a heterogeneous group of neo-plastic illnesses that emerge
through clonal proliferation of lymphocytes in the skin. They are zytomorphologically
comparable to lymphomas in other locations, such as gastrointestinal or nodal locations.
However, due to the variations in the specific micro-environment of the skin, they have
particular, distinctive clinical and histological characteristics, so that the usual
classifications are not always applicable [Burg et al. 1994].
1.2. Classification
Regarding the classification of cutaneous lymphomas a distinction is made between
cutaneous T-cell lymphomas, and cutaneous B-cell lymphomas (Table 1 and 2) [Burg et
al. 1994].
The distinction between T- and B-cell lymphomas is also advantageous from a clinical
point of view, because the prognosis of these two diseases is fundamentally different.
Generally regarding their clinical behavior and their prognosis T-cell lymphomas proceed
more aggressively than cutaneous B-cell lymphomas. The clinical manifestations also
differ: T-cell lymphomas are usually found diffused on the integument, while B-cell
lymphomas frequently appear as solitary lesions.
Table 1 demonstrates the division of cutaneous lymphomas according to WHO
classification [Heenan et al. 1996], Table 2 the current classification of the EORTC.
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Table 1: Classification according to WHO (Heenan et al. 1996)
1. Cutaneous T-Cell Lymphomas
• Mycosis fungoides
• Sézary's Syndrome
• Pagetoid reticulosis
• Adult T-Cell Lymphoma/Leukemia
2. Cutaneous B-Cell Lymphomas
3. Cutaneous Plasmacytoma
4. Pleomorphic Variations of Cutaneous Lymphomas
• Immunoblastic T-Cell Lymphoma
•Large Cell Anaplastic Lymphoma
5. Leukemia with skin involvement
Table 2: Classification according to the EORTC group "Cutaneous Lymphomas"
1996 (Burg et al. 1994)
T-Cell Lymphoma of the Skin
Indolent (survival time>10years)
•Mycosis
fungoides
and
follecular
mucinosis Pagetoid reticulosis
•Large cell CTCL, CD30+ (anaplastic,
immunoblastic, pleomorphic)
•Lymphomatoid papulosis
Aggressive (survival time<5years)
•Sézary's Syndrome
•Large cell CTCL, CD30- (immunoblastic,
pleomorphic)
Temporary
•Granulomatous slack skin
•CTCL pleomorphic, small/medium sized
subcutaneous
panniculitis
like
T-cell
lymphoma (Burg et al. 1991)
B-Cell Lymphomas of the Skin
Indolent (survival time>10 years)
•Follicle center cell lymphoma
•Immunocytoma (including marginal zone
B-cell lymphoma)
Intermediary (survival time>5 years)
•Large B-cell lymphoma of the leg
Provisional
•Intravascular CBCL
•Plasmacytoma
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2. T-Cell Lymphomas of the Skin
A concept is being pursued in Europe that in accordance with the Kiel classification of
nodal lymphomas, uses the cytomorphology to divide the T-cell lymphomas into different
subgroups. However, the clinical course is considered as well (Table 2).
2.1. Mycosis fungoides
Mycosis fungoides is the most common malignant lymphoma. The illness demonstrates
a
typical clinical course. Initially stage it shows a slowly progressing patch stage that looks
like a chronic derreatitis. During its transition into the “plaque stage” the lesions become
thicker and consequently palpable. With progression the “tumor stage” develops, which
is
marked by light red or brownish-red nodes with a tendency towards ulceration. The
course of the illness is not necessarily bound to running consecutively through all three
stages. Occasionally the primary tumor stage can appear immediately [Burg, BraunFalco, 1983].
2.2. Sézary's Syndrome
Sézary's Syndrome is characterized by erythrodermia with pruritus, swelling of the lymph
nodes, as well as leucocytosis in the peripheral blood with atypical lymphocytes (Sézary's
cells). Today, the illness is regarded as a leukemic variation of Mycosis fungoides. The
leucocyte count is normally between 10.000 and 50.000 (up to 100.000 leucocytes/ml).
Typical symptoms are: A therapy-refractory palmoplantar keratosis as well as a diffuse
alopecia. The prognosis is worse than for Mycosis fungoides.
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2.3
CD30+ Large Celled T-Cell Lymphomas of the Skin
Although the histological characteristics presented by the CD30+ large peripheral
(pleomorphic or anaplastic) T-cell lymphomas and by the nodal CD30+ anaplastic
lymphomas are similar, the prognoses are very different.. Nodal lymphomas with this
phenotype show a most unfavorable prognosis, whereas the prognostic outlook for the
CD30+ T-cell lymphomas of the skin is very favorable. Because of the characteristic
similarities primary cutaneous CD30+ lymphomas are often treated just as aggressively
as nodal lymphomas, even though their biology is completely different, as is further
demonstrated by the absence of t(2,5) translocation. (DeBruin et al. 1993)
3. B-Cell Lymphomas of the Skin
B-cell lymphomas make up 25% of all cutaneous lymphomas. In contrast to T-cell
lymphomas they show a relative homogenous clinical course, in contrast to the T-cell
lymphomas. Most of the time a quick growing solitary tumor presents itself clinically.
Multiple tumors are uncommon and, normally, there are no extracutaneous
manifestations. Consequently, mortality rates tend to be low.
4. Diagnosis
Although the majority of skin lymphomas can be identified clinically, it is still essential
to
perform histological and immunohistological examinations. Molecular biological
procedures have become increasingly important for diagnosing and classifying malignant
lymphomas of the skin as well as for distinguishing them from reactive lymphocytic
infiltrates.
4.1. Biopsy/Histology
A sample excision of an untreated clinically suspicious cutaneous area is recommended
for diagnosis and, under certain circumstances ,several sample biopsies may be
necessary. If there is the suspicion of a malignant lymphoma a sample biopsy for routine
paraffin fixation and for cryofixation should always be obtained.
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4.2. Molecular Biological Examinations
Monoclonality can be proven on the DNA-, mRNA and protein level by analyzing the Tcell receptor genes or the immunoglobulin genes and gene products.
The southern-blot technique can be applied for lesions with a very dense lymphocytic
infiltrate. However, the sensitivity of this method is often insufficient so that employing
PCR (polymerase-chain reaction) is often necessary.
Table 3: Staging Investigations in Cutaneous Lymphoma
Clinical Investigations
•Documentation of cutaneous findings
•lymph node palpation (if necessary lymphnode sonography).
•Palpation of liver and spleen.
•Useful: photo-documentation.
Diagnostics with Technical Investigations
•Abdominal sonography.
•Chest x-ray-film on 2 levels.
• Useful for some cases: Thorax-CT,
Abdomen-CT and other image-producing
procedures.
Laboratory Tests
•Complete routine laboratory test (ESR,
blood cell-count, differential blood cellcount, liver enzymes, kidney parameters,
LDH, electrolytes, electrophoresis).
For B-Cell Lymphoma
•Serum and immunoelectrophoresis.
•bone marrow biopsy.
For T-Cell Lymphoma
•Blood smear on Sézary's cells.
•Sample biopsy of affected cutaneous
areas.
•• Useful for some cases: Biopsy from
enlarged lymph nodes and organs.
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5. TNM Stages of the Cutaneous Lymphomas of the Skin
The TNM classification is used to describe the different stages of cutaneous lymphomas.
This classification is also important for the prognosis [Bunn, Lamberg, 1979; Kerl,
Sterry,
1987]. It is important to note that T-cell lymphomas especially have a very favorable
prognosis for the early stages (Ia-IIa) as a rule with survival periods of approximately 1020 years.
In the more advanced stages (Stage III, Sézary's Syndrome) the prognosis is far less
favorable. The expected survival time is 3 years.
There are no standard, commonly accepted standardized TNM classifications and stage
descriptions for cutaneous lymphomas as yet. In 1987 Kerl and Sterry proposed a
classification for T-cell lymphomas (Table 4). A modified version based on that proposal
was recommended in the TNM Supplement 1993 (UICC 1993) for further testing.
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Table 4: TNM Classification and Stage Descriptions for Cutaneous T-Cell
Lymphoma established by Kerl and Sterry 1987
Category
Definition
T: Skin
T0
Lesions clinically and /or histologically suggestive of CTCL
T1
Eczematous patches, plaques:<10% of the body surface
T2
Eczematous patches, plaques:>10% of the body surface
T3
Tumors (more than one)
T4
Erythrodermia
N: Lymph Nodes
N0
No palpable adenopathy
N1
Palpable adenopathy; lymph node pathology negative for CTCL
N2
No palpable adenopathy; lymph node pathology positive for CTCL
N3
Palpable adenopathy; lymph node pathology positive for CTCL
B: Peripheral Blood
B0
No atypical lymphocytes in the peripheral blood (<5%)
B1
Atypical lymphocytes in the peripheral blood (>5%)
M: Visceral Organs
M0
Visceral organs are not involved
M1
Histologically confirmed visceral involvement
Stages
T
N
M
IA
1
0
0
IB
2
0
0
IIA
1/2
1
0
IIB
3
0/1
0
III
4
0/1
0
IVA
1-4
2/3
0
IVB
1-4
0-3
1
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Table 5: UICC-Suggestion for the Classification of Cutaneous T-Cell Lymphoma
(UICC 1993)
(The classification is applicable to all types of cutaneous T-cell lymphomas)
Category
Definition
T: Primary Tumor
TX
Primary tumor can not be evaluated
T0
No indication of primary tumor
T1
Limited plaques, papula or eczematous
patches, covering less than 10% of the
body surface
T2
Disseminated plaques, papula or
erythematous patches, covering 10 % or
more of the body surface
T3
Tumors (one or more)
T4
Generalized erythrodermia
N: Lymph Nodes
NX
Regional lymph nodes cannot be evaluated
N0
Regional lymph nodes are not involved
N1
Regional lymph nodes are involved
M: None Regional Extracutaneous Involvement
MX
Non-regional extracutaneous involvement
cannot be evaluated
M0
No non-regional extracutaneous
involvement
M1
Non-regional extracutaneous involvement
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Stages
T
N
PN
M
IA
1
0
0,X
0
IB
2
0
0,X
0
IIA
1/2
1
0,X
0
IIB
3
0/1
0,X
0/1
III
4
0/1
0,X
0
IVA
1-4
0/1
1
0
IVB
1-4
0/1
0/1
1
6. Therapy
Since cutaneous malignant lymphomas are a very heterogeneous group of illnesses,
generally applicable guidelines for their treatment are not available. This situation is
further aggravated by the fact that there are almost no controlled prospective studies that
could provide reliable data on the dosage, time period, or effective combinations for the
treatment of cutaneous lymphoma. In any case, the treatment of cutaneous T-cell
lymphomas (CTCL) [Dummer et al. 1996, Jörg et al. 1994, Kalinke et al. 1996] must be
differentiated from the treatment of cutaneous B-cell lymphomas.
Today a fairly conservative treatment adjusted to the stage of the illness is recommended
for CTCL ( see Table 6). In the early stages localized treatments such as topical steroids,
PUVA (psoralen plus UVA), locally applied cytostatic agents like BCNU, or radiation
therapy with fast electrons or soft x-ray therapy predominate. In the advanced stages
systemic therapies, such as a combination of PUVA therapy with retinoids or
recombinant
interferon-alpha, are indicated. For patients with leukemia (Sézary's Syndrome) it
appears that the extracorporal photopheresis, which has few side effects, leads to a
remission in approximately 50% of the patients. [Heald et al. 1992]. This treatment is
especially effective in combination with interferon-alpha or retinoids. In the late stages, a
palliative chemotherapy could also be tried, considering that a life-prolonging effect has
never been convincingly demonstrated. Moreover the treatment leads to further
immunosuppression and to an increase in infectious complications. Table 5 shows the
recommended procedure for a treatment that is adapted to the stage of the illness.
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Primary cutaneous B-cell lymphomas without any other organic manifestations have a
more favorable prognosis than the nodal B-cell lymphomas, even if they are
histologically
classified as "highly malignant." For this reason, a localized treatment is sufficient in
many
cases. Surgical removal or radiotherapy ("soft" x-ray therapy 6-10x 200 cGy, 50 kV, 2x a
week, fast electrons 4000 Gy) (Goldschmidt 1991) is to be considered. For multiple
lesions, PUVA treatment can be tried as well. Only if there are extracutaneous
manifestations should polychemotherapy be undertaken by a hematologist/oncologist
[Joly et al. 1991].
6.1. Surgical Therapy
Since these tumors respond so well to radiation and since radiation treatment also leads
to good cosmetic results, surgical treatment is only justified in a few individual cases.
Surgical therapy can become necessary for solitary lesions of pleomorphic CTCL (often
CD30+) or solitary lesions of B-cell lymphomas of the skin. In both cases surgery can
sometimes be curative. A surgical margin of 0.5-1,0 cm is recommended for the excision.
Table 6: Recommendations for a stage adapted therapy of CTCL (Dummer et al.
1996)
Stage
Therapy
Stages Ia,Ib and IIa
•PUVA (psoralen (5-methoxypsoralen 1.2
mg/kg or 8-methoxypsoralen 0,8-1,2 mg/kg
body weight) two hours before UVA 0.5-0,6
J/cm
2
/3x a week) possibly in combination
with 0,5-1 mg acitretin/kg (Re-PUVA).
•Application of carmustine (BCNU) to the
whole body, 5 mg in unguentum cordis for
three days every two weeks (cave
thrombocytopenia).
If there is progress
•PUVA with IFN-α (3-9 million I.E. s.c. 3x a
week) 0,5-1 mg acitretin/kg body weight
with IFN-α (3-9 million I.E. s.c. 3x a week).
•Fast electrons applied to the whole body
(up to 3000 Gy overall dosage).
•Methotrexat 7-20mg/m
2
body surface, 1x a
week.
Stage IIb
•PUVA with IFN-α or acitretin with IFN-α as
above combined with soft radiotherapy.
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(therapy 6-10x 200 cGy, 50 kV, 2x a week).
•Electron beam irradiation
If there is progress
Chemotherapy with
•(Knospe-Regimen)(chlorambucil 0,4 to 0,7
mg/kg body weight distributed over days 1
to 3 p.o.; predisolon 75 mg day 1, 50 mg
day 2, 25 mg day 3 p.o.) Repetition from
day 15 on.
•COP (vincristine 1,4 mg/m
2
body surface
max. 2 mg i.v. day 1; cyclophosphamide
400 mg/m
2
body surface i.v. days 1-5,
prednisolon 100 mg/m
2
body surface days
1-5 p.o.) Repetition from day 29 on.
•CHOP (cyclophosphamide 750 mg/m
2
body surface i.v. day 1; adriamycin 50
mg/m
2
i.v. day 1; vincristine 1,4 mg/m
2
body
surface max. 2 mg i.v. day 1; prednisolon
100 mg/m
2
day 1-5 p.o., Repetition from
day 29 on.
if high grade histology is determined, the
following should possibly be performed
•COPBLAM (cyclophosphamid 400 mg/m
2
i.v. day 1; vincristine 1,0 mg/m
2
day 1,
prednisolon 40 mg/m
2
day 1-10 p.o.,
bleomycin 15 mg i.v. day 14, adriamycin 50
mg/m
2
i.v. day 1, procarbazin 100 mg/m
2
day 1-10 p.o.; Repetition from day 22 on.
Stage III (includes Sézary's Syndrome)
•Photopheresis (day 1 and 2 every 4
weeks). If there is no remission, additionally
IFN-α (3-9 million I.E. s.c. 3x a week)
possibly plus 0,5-1 mg acitretin/kg body
weight.
•Methotrexat 7-20 mg/m
2
, 1x/week.
•PUVA with IFN-α as above.
If there is progress
•Palliative PUVA.
•Electron beam irradiation.
•Distant radiation therapy.
•Chemotherapy as above.
•experimental therapies (interleukin-2fusion toxins).
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Stage IVa, IVb
•Palliative therapy with chemotherapy (as
above).
•Possibly combined with IFN-α or retinoids
(compare above).
•Photopheresis for patients with leukemia.
•Or experimental therapies.
6.2 Photo-Therapy
Photo-therapy with PUVA (psoralens with UVA, dosage see Table 5) is a very important
measure for treatment of indolent T-cell lymphoma of the skin [Hönigsman et al. 1984].
For the treatment of CTCL patients at stage III (includes Sézary's Syndrome) the extracorporeal photopheresis has become the established therapy. For this therapy blood is
extracted after psoralens have been ingested. The blood is then divided into serum
fraction red blood cells and white blood cells by means of centrifugation. While the
erythrocytes and the serum fraction are immediately reinfused, the white blood cell
(leukocyte fraction) mixture containing the psoralen is being irradiated with UVA before
reinfusion.
6.3 Immunotherapy
For the treatment of CTCL retinoids and interferon are often used. This therapy is
probably successful because of the immune modulating properties of these two
substances. Originally the dosage of interferon and retinoids was set very high [Bunn et
al. 1994]. Today, such high doses don't seem to be necessary, especially when a
combination of these substances is applied. As a guideline a standard dosage of 9 million
I.E. Interferon-α three times a week and .5 mg. - 1 mg/kg body weight acitretin can be
used. Probably even lower doses can be applied if both substances are combined.
6.4 Chemotherapy
Clinical experience has shown that polychemotherapy is not completely curative, even
when combined with bone marrow transplantation. Therefore, this therapy should be
reserved for palliative treatment in the advanced stages; whereby a less aggressive
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therapy should be tried first, for example, the "Knospe-Regimen". Only at later stages
should CHOP or COPBLAM be used (see Table 5) [Bunn et al. 1994].
6.5. Radiotherapy
For localized cutaneous lymphoma (e.g. tumors with MF or B-cell lymphoma) the soft
xray therapy (dermopan, 6-10X 200 cGy, 50 KV, 2X per week) with 20-50 kV is still a
very
efficient therapy with comparatively few side effects. Radiotherapy is also suitable for
extensive lymphoma manifestations with a diameter of 10 cm or more. This form of
treatment can easily be combined with a systemic administration of interferon, retinoids,
methotrexat or chemotherapy [Bauch et al. 1995].
For some of the patients with Mycosis fungoides a long lasting remission can be
achieved through electron beam irradiation. However, this treatment should only be
applied in advanced stages. Generally 30 to 40 Gy are applied in fractions of 1,5 to 2,0
Gy 3 to 4 times a week as a total body treatment. [Cotter et al. 1983; Micaily et al. 1990].
in the advanced stages a treatment with dosages ranging between 1500-3000 Gy can be
used to achieve a palliative effect [Cotter et al. 1983]. If less than 10% of the integument
is involved the therapy can be applied as a curative measure [Quiros et al. 1996]. This
technique is, however, very expensive and a linear accelerator that can produce fast
electrons with an energy level of 4-18 MeV is needed.
7. Follow-Up Evaluation
There are no guidelines for follow-up evaluations that are backed up by solid data. In
early stages (I and II) semiannual or annual clinical examinations seem sensible. In the
advanced stages (III and IV) examinations every 4-6 weeks should be considered in
order to evaluate the success of the treatment more effectively. The intervals between
follow-ups for patients with cutaneous lymphoma depend on the general clinical picture.
In any case, a new sample biopsy is called for when there are changes in clinical
manifestations of the lymphoma or if new lesions appear within a short time period.
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8. References
1. Bauch B, Barraud-Klenowssek M, Burg G, Dummer R (1995) Eindrucksvolle
Remission einer Mycosis fungoides im Tumorstadium unter low-dose Interferon-a
und Acitretin nach erfolgloser Chemotherapie. Z Hautkr 70:200-203
2. Bunn PA, Jr., Lamberg SI (1979) Report of the Committee on Staging and
Classification of Cutaneous T-Cell Lymphomas. Cancer Treat Rep 63:725-8
3. Bunn PJ, Hoffman SJ, Norris D, Golitz LE, Aeling JL (1994) Systemic therapy of
cutaneous T-cell lymphomas (Mycosis fungoides and the Sezary syndrome). Ann
Intern Med 121:592-602
4. Burg G, Braun-Falco O (1983) Cutaneous lymphomas, pseudolymphomas and
related disorders. Berlin, Heidelberg, New York, Tokyo: Springer
5. Burg G, Dummer R, Kerl H (1994) Classification of cutaneous lymphomas. Derm
Clinics 12:213-217
6. Burg G, Dummer R, Wilhelm M, Nestle F, Ott MM, Feller A, Hefner H, Lanz U,
Schwinn A, Wiede J (1991) A subcutaneous delta-positive T-cell lymphoma that
produces interferon gamma. New Engl J Med 325: 1078-1081
7.
Cotter GW, Baglan RJ, Wasserman TH, Mill W (1983) Palliative radiation treatment
of cutaneous Mycosis fungoides--a dose response. International Journal of
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8. deBruin P, Beljaards RC, van HP, Van DVP, Noorduyn LA, Van KJ, Kluin NJ,
Willemze R, Meijer CJ (1993) Differences in clinical behaviour and
immunophenotype between primary cutaneous and primary nodal anaplastic large
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9. Dummer R, Häffner AC, Hess M, Burg G (1996) A rational approach to the therapy
of cutaneous T-cell lymphomas. Onkologie 19:226-230
10. Goldschmidt H (1991) Radiation therapy of other cutaneous tumors. Berlin,
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11. Heald P, Rook A, Perez M, Wintroub B, Knobler R, Jegasothy B, Gasparro F,
Berger C, Edelson R (1992) Treatment of erythrodermic cutaneous T-cell
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12. Heenan P, Elder D, Sobin L (1996) Histological typing of skin tumors. 2nd ed. WHO
international classification of tumours. Berlin, Heidelberg, New York, Tokyo:
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13. Hönigsmann H, Brenner W, Rauschmeier W, Konrad K, Wolff K (1984)
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fungoides: follow-up study of 52 patients. J Clin Oncol 9: 1994-2001
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16. Kalinke D-U, Dummer R, Burg G (1996) Mangement of cutaneous T-cell
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17. Kaye FJ, Bunn PJ, Steinberg SM, Stocker JL, Ihde DC, Fischmann AB, Glatstein
EJ, Schechter GP, Phelps RM, Foss FM, Parlette H, Anderson M, Sausville E
(1989) A randomized trial comparing combination electron-beam radiation and
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Engl J Med 321: 1784-90
18. Kerl H, Sterry W (1987) Classification and staging. In: EORTC/BMBF Cutaneous
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lymphomas (G. Burg and W. Sterry, eds.) pp 1-10
19. Micaily B, Campbell O, Moser C, Vonderheid EC, Brady LW (1991) Total skin
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20. Quiros PA, Kacinski BM, Wilson LD (1996) Extent of skin involvement as a
prognostic indicator of disease free and overall survival of patients with T3
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21. Wood GS, Haeffner AC, Dummer R, Crooks C (1994) Molecular biology techniques
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