Cutaneous lymphomas
Summary
Cutaneous lymphomas are a heterogeneous group from a clinical point of view,
Morphological, molecular, evolutionary and prognostic, and therapeutic. The classifications
Recent developments take account of these specificities, giving particular importance to the
Their prognostic value. While the prognosis and response to treatment are favorable
In the so-called low-grade chronic forms, recent therapeutic innovations,
Particularly on biotherapies, seem to be able to improve the prognosis of the
Most serious forms, as is the case for rituximab (monoclonal anti-CD20 antibody)
In disseminated forms of cutaneous B-lymphoma, and for alemtuzumab (antibodies
Monoclonal anti-CD52) in refractory forms of cutaneous T-lymphoma. The elucidation of
Molecular mechanisms involved in the pathophysiology of these lymphomas should open
New therapeutic perspectives in the near future.
Definition
Primary cutaneous lymphomas, the most frequent of extraganglionnaires lymphomas after
Digestive lymphomas, constitute a heterogeneous entity by their clinical characteristics,
Histological, phenotypic, Molecular and prognostic. 1
Their natural history and
Molecular anomalies that characterize them are different from those of T
Ganglion. The ancient classifications of Kiel, the working formulation or the REAL
(Revised European American Lymphoma Classification), established for lymphomas
Ganglion, have been replaced by a classification taking into account the specific
Primary cutaneous lymphomas, which was proposed by the EORTC group (European
Organization for research and Treatment of cancer) and has enabled the definition of
Classified in prognostic-value groups. These specificities were
Recognized and integrated into the recently updated classification by the world Organisation
of health. 1
2
Cutaneous T-lymphomas
Cutaneous T-lymphomas (v. Table) are the most common of the primary cutaneous lymphomas,
Whose épidermotropes lymphomas constitute the predominant entity, combining
Mainly mycosis Fungoides and sezary syndrome. 2
Forms of good prognosis
Mycosis Fungoides
The ÉPIDÉMIOLOGIQUES3 data
Regarding épidermotropes cutaneous T lymphomas are little
Many. Studies conducted in the United States report an annual rate of 1973 to 1992
of 0.36/105
Between the beginning of the years 1970 and that of the years 1990.
For Sezary syndrome, the incidence would be 30 to 40 new cases per year in the United States.
No prevalence data is currently available. The incidence of mycosis fungoides
Predominates in the second half of life, rising from 0.1/105
/year before 30 years, at 1/105
/year
After 60 years, although cases have been described in the child. 3
There is a predominance
Male.Psoriasis (but not atopic dermatitis or contact eczema) has been identified as
A risk factor of mycosis fungoides, with a relative risk (RR) of 3, without knowing
If it is the affection or its treatment that would promote the occurrence of lymphoma. No relationship
Causality could not be demonstrated with a professional or environmental factor.
Mortality rates in the order of 0,065/105
Have tended to decrease between 1979 and
1991 and the trend seems to be confirmed. Mortality has the same modulation as incidence, by origin and sex, but the numbers are questionable since all deaths
By Mycosis Fungoides are not listed.
Some viruses, such as the Retrovirus HTLV-1 (Human T cell leukaemia virus type 1), have been
Suspected of playing a role in the oncogenesis of cutaneous lymphomas, but this hypothesis
has not been confirmed. The same is the role of Superantigens. 4
The Mycosis fungoides (Fig. 1), in its typical so-called progressive form, follows an evolution
Chronic, with a long-exclusively cutaneous injury that was initially characterized by
Macules erythematous, then plates often squamous, with figured outlines. After
A variable duration, often several years, the lesions may become infiltrated, or
Still broadcast and conflate to lead to a erythrodermic state. nodules or tumors
May also appear either on pre-existing infiltrated lesions or in skin
Previously healthy. These tumors can ulcerate and their histological analysis then shows
Often a histological transformation, defined by the presence of more than 25% of
Large cells within the infiltrate (Mycosis Fungoides transformed). This transformation has a
Pejorative prognostic value, particularly in the case of ganglionic or visceral harm. 5
Among
The other forms of mycosis fungoides or variants, we distinguish the mycosis fongoïdes
Folliculotropes, the reticulosis Pagétoïde where the infiltration is exclusively épidermotrope, and the
Chalazodermie granulomatous.
Diagnosis
It can be difficult in the initial stages. The Mycosis fungoides is characterized by an infiltration
Dense dermal comprising lymphocytes with cérébriforme and hyperchromatic nuclei
corresponding to sezary cells. They also sit in the epidermis
(épidermotropisme), and typically form Thecae intraepidermal called Also
Microabscess of Pautrier. These atypical cells have a mature T-phenotype, CD3 +
, CD4 +, CD8 ¯,
and CD45R0 +
. There are sometimes anomalies of expression of antigens of differentiation of
Mature T lymphocytes, including a possible loss of expression of CD2 or CD5, especially
In the advanced stages. The appearance of tumors is sometimes accompanied by a lack of
of Épidermotropisme.
Prognosis
The overall prognosis of Mycosis Fungoides has improved over the last few decades. The
Major prognostic factor is the T-stage of the TNM classification (tumour nodes metastasis).
Thus, 5-year specific survival rates of T1 stages (macules or plaques on less than
10% of body surface), T2 (more than 10%), T3 (tumors), and T4 (toxic) are
Of nearly 100%, 67 to 96%, 50 to 80%, and 40% respectively. The existence of a
Blood Hypereosinophilia is a derogatory factor. 6
Treatment
Local chemotherapy (chlormethine [Caryolysine] or carmustine) or Puva are
specified in stages T1 and T2; Radiotherapy, interferon alpha (IFNα), Bexarotene
(Targretin) or chemotherapy (CHOP protocols [Cyclo-vincristine (Oncovin), Prednisone],
ESHAP [etoposide, solved-medrol, high dose of cytarabine, cisplatin] or gemcitabine [Gemzar]
In case of failure) are indicated in tumor stages. The érythrodermiques stages are
Treated with topical chemotherapy, IFNα, methotrexate, Bexarotene or by alemtuzumab
(MabCampath). 7
4
Lymphoproliférations T cutaneous CD30 +
This group, the second in order of frequency since it represents about 30% of the
Cutaneous T-lymphomas, mainly includes primary cutaneous T-lymphomas with large
CD30 + anaplastic cells
and the Lymphomatoid papulosis.
anaplastic large cell primitive cutaneous T lymphomas
They are the result of the proliferation of large cells anaplastic, immunoblastiques or
Pleomorphic, the majority of which express the CD30 antigen.
Lesions, most often papules of nodules or tumors, are either isolated or
Localized They can ulcerate and regress spontaneously. Skin Forms
Disseminated are possible, while the outskin damage is rarer,
essentially ganglion.
Diagnosis
Tumor infiltration is located in the dermis, without épidermotropisme. The majority of the
Case of anaplastic cells of CD4 + phenotype
, with a frequent expression of molecules
Having a cytotoxic function like Granzyme-B, TiA-1 and Perforin. Unlike the
Secondary forms, primitively cutaneous forms do not or rarely express the kinase
ALK (anaplastic lymphoma kinase), which is associated with a translocation 2; 5.10
Prognosis
Overall favorable, with a specific survival at 10 years which is more than 90%. 11 The
Diseases with locoregional ganglionic impairment appear to have a prognosis identical to
Those with exclusive skin damage. 11
Treatment
Radiotherapy or surgical resection are adapted in case of a single lesion or lesions
Located. Multifocal forms can be treated with IFNα, methotrexate or Bexarotene.
Disseminated forms should be treated with CHOP-type polychemotherapy, ABVD
(Adriblastine, bleomycin, Vinblastine, dacarbazine), ESHAP, or gemcitabine.
The Lymphomatoid papulosis
It is a papulonécrotique eruption that evolves spontaneously regressive,
With a suggestive histology of a cutaneous lymphoma, rather of the type anaplastic CD30 +
. She
Can be seen at any age, but predominates in the young adult. The lesions regress in a few
Weeks leaving a scar often. Lymphomatoid Papulosis can sometimes be Bachelez
Associated with a fungoides mycosis or Hodgkin's disease. 12 in these cases associated with a
Lymphoma, molecular analyses of clonality have shown the existence of rearrangements
Of the TCRγ locus in the 2 types of lesions. 12Diagnosis
Tumor infiltration is made up of atypical cells that are usually large in size and
The so-called Sternbergoïde (Type A), cérébriformes nuclei resembling the cells of the
Mycosis fungoides (Type B). An infiltrate Lymphadenitis, Neutrophilic and Eosinophilic is
Gladly associate. Tumor cells have the same phenotype as those of lymphomas T
Anaplastic CD30 + in type A, and the same as those of the Mycosis fungoides in the
Type B.
Prognosis
Excellent, with a 5-year specific survival rate of 100%. The incidence of lymphoma with
Location is less than 5%. 11
Treatment
Puva or topical chemotherapy (Caryolysine or carmustine) are
Usually used first-line. In diffuse forms in the event of relapse or
of resistance, weekly low-dose methotrexate may be indicated.
Forms of bad prognosis
Sezary's syndrome
Sezary syndrome is a much rarer entity than mycosis fungoides, and
of globally pejorative evolution. According to the criteria defined by the International Society for
Cutaneous Lymphomas (ISCL), the diagnosis is based on the presence of at least one of the criteria
Following: Number of circulating sezary cells greater than 1000/mm3
On the smear
Blood CD4/CD8 ratio greater than 10 with increased lymphocyte count
and/or loss of expression of pan-T markers or CD26; Presence of a clone T
Blood with increased number of circulating lymphocytes; Presence of a clone T
Blood with cytogenetic abnormalities.
Sezary syndrome (Fig. 2) combines a very itchy infiltrated toxic, and
Often a superficial polyadénomégalie.
Diagnosis
The appearance is often quite comparable to the Mycosis
Fungoides at the stage of plaques or toxic.
However, Épidermotropisme is often less marked in the
Sezary syndrome, and the diagnosis is sometimes
Difficult at first. The presence of sezary cells of
Large size for the cytological examination of the blood and/or
Ganglion is an important argument; They have a phenotype
Similar to that of mycosis fungoides cells, with a
Frequent loss of expression of CD7 and CD26. This is
of clonal expansion, and detection by study in
Polymerase chain reaction (PCR) of the TCRγ locus
Predominant and identical clonal rearrangement in the
Skin lesions and in the blood provides important help
Diagnosis in difficult cases.
6
Prognosis
Overall derogatory, with a median of survival from 2 to 4 years. Infections, especially
Starting point, as well as opportunistic infections are the main cause of the
Of death.
Treatment
Associations of chlorambucil and prednisone, or methotrexate, are seldom and then
Only transiently effective, the sezary cells being remarkably resistant to
Cell death induced by cytotoxic agents. 8
Alpha Interferon can provide
Remissions that are seldom complete and durable. The same is the
The two treatments can also be associated. 9
More
Recently, clinical studies have reported the efficacy of alemtuzumab, antibodies
humanized monoclonal anti-CD 52.7
Peripheral cutaneous T-lymphomas
These are non-épidermotropes lymphomas characterized by the predominance of cells
of T-phenotype CD4 +
, small or medium size. These cells do not express the antigen
CD30.
They are mainly observed in adults, in the form of nodules or tumors, unique or
Multiple.
Diagnosis
The cells, pleomorphic of medium or large size, or of immunoblastic appearance,
Express a CD4 + T phenotype
. In some cases, a large contingent of cells,
Representing less than 30% of the infiltration, can be observed. An epidermal exocytosis made of
Isolated cells is also possible, can sometimes pose a problem of diagnosis
Differential with a fungoides mycosis.
Prognosis
Quite pejorative, even in forms with isolated lesions, with about 20% survival at 5 years.
Treatment
The polychimiothérapies of type CHOP or ESHAP, or the gemcitabine in case of
Of failure are indicated in these forms.
Uncertain prognosis Forms
Small-size pleomorphic cell cutaneous T-lymphomas
Average CD4 +
These are non-épidermotropes lymphomas characterized by the predominance of cells
of T-phenotype CD4 +
, small or medium size. These cells do not express the antigen
CD30.
The condition can be seen at any age, but predominates in adults. It is either a plate
Or a single nodule, or multiple diaper-nodules.
Diagnosis
The cells infiltrate the dermis in the form of a dense, nodular infiltration composed of
T lymphocytes of small or medium size, T-phenotype CD4 +
. In some cases, a
Large cell quota, representing less than 30% of the infiltration, can be
7
Observed. Epidermal exocytosis made of isolated cells is also possible, which can
Sometimes pose a differential diagnosis problem with a fungoides mycosis.
Prognosis
Pretty good, with 60 to 80% specific survival at 5 years.
Treatment
The localized forms are covered by radiation therapy. In multiple-lesion forms,
Interféronalpha or cyclophosphamide are proposed for first-line purpose.
Panniculitis-Type subcutaneous T-lymphomas
These are rare forms of cutaneous T-lymphomas, T-phenotype, TCRαβ +
, CD8 +
Cytotoxic, which can complicate a macrophage activation syndrome.
This form is also observed at any age, in the form of nodules or plaques. Signs
Generals are possible (fever, sweats, asthenia).
Diagnosis
Infiltration sits essentially, if not exclusively, in the Hypodermis, in the form of a
infiltrates pleomorphic with often images of necrosis, and cytophagocytose. 13 This aspect
May be long preceded by a panniculitis of benign appearance, with inflammatory infiltration
Important.
Prognosis
Initially regarded as very pejorative, it seems in fact characterized by an evolution
Recurrent, chronic, and 5-year-old survival near 80%. 14
Treatment
In disseminated severe forms, accompanied by Hémophagocytaire syndrome, the
Polychemotherapy (CHP, ESHAP) is required. In the more chronic forms, the
Corticosteroids can allow control of the disease.
T-NK cutaneous lymphomas called "nasal type"
These are rare forms of cutaneous T-lymphoma, natural killer (NK) phenotype, or
Much more rarely CD8 +
which can be complicated by a syndrome
Activation macrophage.
Nodules or plaques are readily seated on the trunk or mid-facial region, and
Ulceration is common. General signs, a Hémophagocytaire syndrome, or a
Association with NK leukemia are possible.
Diagnosis
Infiltration sits in the dermis and Hypodermis, often with angiocentrique topography, and
of angiodestructeur appearance. The cells are either of the ¯ CD3 phenotype, CD2 +
, CD56 +
(Phenotype
NK), or CD3 +
Cytotoxic. Detection of Epstein-Barr virus in lesions is very
Frequent. 15 there is a variant affecting the child, associated with the Epstein-Barr virus, which is
observed mainly in Asia and Latin America, and poor prognosis.
Prognosis
Very severe, with a median survival of a few months.
Treatment
Polychemotherapy is the rule, but it is not effective.
Other cutaneous T-lymphomas 8
This entity is a group of different forms whose characterization and prognostic value are
Still uncertain, or unclassifiable forms. These include cutaneous T-
Épidermotropes CD8 +
,16 aggressive evolution and cutaneous phenotype T lymphomas
TCRγδ, also bad prognosis.
Blastic lymphomas with NK cells
Initially considered a proliferation derived from a NK precursor, their origin
Currently admitted is that of the Plasmacytoïdes dendritic cell line. 17
Lesions are made up of one or more nodules, sometimes with a
Ganglionic.
Diagnosis
Dermal infiltration is made up of CD3 phenotype cells ¯, CD56 +
, TCL1 +
, CD123 +
Cytotoxic.
Treatment and Prognosis
The prognosis is dark, despite the chemotherapy, the relapses are often early.
Cutaneous B lymphomas
Cutaneous B lymphomas of the marginal zone
These lymphomas, 1
Of chronic evolution, are composed of small B-lymphocytes of Allure
Centrocytic lymphoma, lymphoplasmocytaires cells and plasma, which include cases of
Previously described under the term immunocytomes. They belong to the larger entity
Lymphomas of the marginal zone which affect in particular mucous membranes (mucosaassociated
lymphoid tissue [MALT]).
lesions, nodules or plaques are readily manifold. Ganglionic damage is
Exceptional. An association with a Borrelia burgdorferi infection has been reported.
Diagnosis
The dermal nodular infiltration is often accompanied by reaction germ centers.
The cells in the marginal Zone Express CD20, CD79a, and Bcl-2, but not CD5, CD10, or
BCL-6. Translocations (14; 18) (q32; q21) involving the IgH locus and the MLT gene were
detected, but not the characteristic translocations of the MALT lymphomas.
Prognosis
Excellent.
Treatment
Radiotherapy or surgical excision in isolated lesions, the chlorambucil
(C
Hloraminophène) or interferon alpha in the case of multiple lesions, are the choice of
First-line therapy.
Follicular lymphomas primitively cutaneous
The primitively cutaneous follicular lymphomas consist of centrocytes (small and
Large cells cleaved) and a variable proportion of centroblasts (large non-
cleaved to voluminous Nucleoli), with follicular, follicular and diffuse architecture, or
Broadcasts.
They form nodules or plaques typically located on the head or trunk,
of chronic evolution. Ganglionic damage is possible.
9
Diagnosis
Dermal infiltration is composed of B cells expressing CD20, CD79a, and bcl6, but not
CD5, and not or little Bcl2. The expression of CD10 is observed in cases where the architecture is
Follicular. A monotypical expression of immunoglobulin light chain is possible, and
A clonal rearrangement of the IgH locus is usual.
Prognosis
Very good, with a 5-year survival of 95%.
Treatment
Radiotherapy in localized forms, chemotherapy in disseminated forms
Are first-line treatments, the Autograft may also be proposed. 18 of the
Positive results were obtained with rituximab (Mabthera), alone or in association with
Chemotherapy.
"Leg type" large cell skin lymphomas
They are the result of the proliferation of centroblasts and immunoblasts and often affect
Older subjects. The lesions typically sit on the legs (Fig. 3), sometimes in another
localization, in the form of erythematosus or purplish nodules. Unlike forms
Follicularis, the spread of the skin is not uncommon and poor prognosis.
Diagnosis
Infiltration is diffuse, deep, composed of cells
Large size with images of mitosis. The
Tumor cells express CD20 and CD79a, BCL-2
and Bcl-6, but not CD10. Treatment and Prognosis
Treatment with polychemotherapy including
Anthracyclines is indicated, the association with the
Rituximab being suggested by recent studies.
5-year survival is estimated at 55%, the spread of
Lesions and ganglionic damage being
Bad prognosis. 19
Other large cell diffuse cutaneous B lymphomas
This group includes diffuse lymphomas with large anaplastic cells or
Plasmoblastiques, T-cell-rich b lymphomas, and Intravascular b lymphomas,
The latter may involve pulmonary damage and the central nervous system,
Bad prognosis. 1
Conclusion
Cutaneous lymphomas are a heterogeneous framework for which different entities have
Specific characteristics, including evolutionary ones, that distinguish between them, and
ganglion forms. The recent characterization of molecular mechanisms involved in
The oncogenesis has opened up promising new therapeutic perspectives. So it was
demonstrated that constitutive activation of the NFκB signalling pathway plays an essential role in the resistance to apoptosis of sezary syndrome cells, which may allow
Therapeutic use of pharmacological inhibitors of this pathway. 20 Other studies have
Demonstrated the expression by cutaneous T-lymphoma cells of variants of certain
Of the family of KIR (killer inhibitory receptors), which can be targets
Therapeutic potential. 21 in cutaneous B lymphomas, the characterization of abnormalities
And molecular genetics has also helped to define potential therapeutic targets,
In order to foresee progress in the treatment and prognosis of the most advanced forms of
Serious.
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