The understanding of skin lymphomas has followed the evolution of lymph node based lymphomas. There has been an explosive growth in the classification of these lymphomas with new insights gained from molecular biology, hematopathology, and immunohistochemistry. Ultimately, the utility of any classification system is to predict behavior of each cancer and help to direct therapy. The EORTC classification is one system that does a fine job of organizing the myriad of names of cutaneous lymphomas. Briefly, cutaneous lymphomas can be divided into T and B cell lineage, with T cell lymphomas the most common. Within these divisions, further distinctions based upon the clinical behavior can be gleaned.
- Adult T-cell leukemia/lymphoma (HTLV-1)
- CD30+ Lymphomas
- Follicular Center Cell Lymphomas of the Skin
- Gamma-Delta Cutaneous T-cell lymphoma
- Granulomatous slack skin
- Intravascular large B-cell lymphoma
- Large B-cell lymphoma of the leg
- Lymphomatoid papulosis
- Mycosis fungoides
- Sezary syndrome
- Subcutaneous panniculitis-like T cell lymphoma
- T-Cell Rich B-Cell Lymphoma of the Skin
It must be remembered that cutaneous lymphomas are relatively rare. Of these variants, mycosis fungoides is the most common and sometimes has been used indiscriminately to describe all cutaneous T cell lymphomas (CTCL). To further complicate matters, there are a few skin rashes which have been classified under CTCL which at best, have an unpredictable behavior with an increased risk of progression to lymphoma. These rashes called parapsoriasis have been broadly divided into small and large plaque parapsoriasis. The name derives from the clinical appearance of these scaly rashes which resemble psoriasis. These rashes were chronic conditions and relatively resistant to therapy. Within recent years, large plaque parapsoriasis (also known as atrophic parapsoriasis, retiform parapsoriasis, and poikilodermal atrophicans vasculare) has become synonymous with mycosis fungoides. Careful studies have found progression to CTCL in 10-30% of cases. The problem is identifying which cases will progress. The lesions usually start as large erythematous patch or plaque on the trunk or extremities, usually 10 cm. or more in diameter. Atrophy may follow and nearly all cases which have progressed to lymphoma have done so through this atrophic stage.
Finally, there are a number of skin diseases which have been broadly classified as pseudolymphomas. These entities mimic cutaneous lymphomas both clinically and histologically but are benign.
The pathogenesis or origin of cutaneous lymphomas is actively debated. One theory suggests an early precursor lesion with a persistent stimulation by an antigen, possibly a superantigen. This leads to epidermal derived growth factors which attract lymphocytes. Additional acquired defects in cell cycle regulation and apoptosis, early CTCL may develop. These neoplastic T-helper-2 cells proliferate because they cannot be blocked by endogenous interferon-gamma because of IFN-gamma resistance. There is a low proliferation rate at this point. With increasing genetic alterations, there is a reduced dependency on epidermal derived growth factors and subsequently a high proliferation rate.
In contrast, cutaneous B cell lymphomas (CBCL) have a different pathogenesis. Like CTCL, they are antigen driven processes. It appears that heavy chain genes (VH) of the B cells show significant mutations. Once this occurs, a neoplastic clone develops. There are definitely some environmental factors associated with this such as Borrelia burgdorferi infection (agent of Lyme disease). The term SALT (Skin Associated Lymphoid Tissue) has been applied to some of these B cell lymphomas, citing the similarity of CBCL with other B cell lymphomas arising within mucosa such as the salivary gland and gastrointestinal tract.
The similarities include:
Nonaggressive clinical behavior
Subtle histologic differences from true follicular center cells and intermediate cells of the lymph nodes
Tumor cells with unimodal morphometric features intermediate between centrocytes and centroblasts of nodal follicular center cells
Characteristic polymorphism of the neoplastic cellular infiltrate
Multiphasic histologic features with the various cell types often intermingled
Frequent CD5- CD10- phenotype of neoplastic B cells
Nerve growth factor receptor+, CD14- CD21 +/- phenotype of associated dendritic cells
Lack of either t(11;14)/t(14;18) translocation or bcl-1/bcl-2 gene and c-myc oncogene rearrangements
SYNONYMS Cutaneous Lymphoma INCIDENCE In a recent survey of cutaneous lymphomas occurring in 755 patients, the frequency distribution of the major diagnostic groups was as follows: LYMPHOMA TYPE PERCENTAGE Mycosis fungoides/Sézary syndrome 82.3 Lymphomatoid papulosis 12.6 CD30+ anaplastic large-cell lymphoma 0.9 Peripheral T-cell lymphomas 2.9 B-cell lymphoma 4.5 AGE RANGE-MEDIAN SEX (M:F) GEOGRAPHY Japan Am J Dermatopathol 2001;22:510-514
Review of 65 pateint cases from 1988-1999 as classified by the EORTC found good correlation between histologic subtypes and clinical follow-up
T-cell receptor beta variable region (V beta) usage in cutaneous T-cell lymphomas (CTCL) in comparison to normal and eczematous skin.
Potoczna N, Boehncke WH, Nestle FO, Kuenzlen C, Sterry W, Burg G, Dummer R.
Department of Dermatology, University of Zurich Medical School, Switzerland.
J Cutan Pathol 1996 Aug;23(4):298-305 Abstract quote
Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of lymphoproliferative disorders.
\We investigated the variable region (V beta) of the T-cell receptor (TCR) repertoire in CTCL and compared it to the V beta repertoire in normal and eczematous skin. We used a panel of 21 anti-V beta antibodies and investigated 84 biopsies of 71 CTCL patients (4 parapsoriasis en grandes plaques (PA), 1 lymphomatoid papulosis, 29 mycosis fungoides (MF), 13 Sezary syndrome (SS), 1 CD8+ CTCL, 11 pleomorphic CTCL (PLEO), 12 CTCL nor classified). Six biopsies of normal skin and 6 of eczematous skin lesions served as controls.
We determined the frequency of the V beta in normal and inflamed skin and compared it to the percentage of the respective V beta in the malignant clone of the CTCL patients. The percentage of the V beta positive CD4+ cells in relation to the total number of T cells in normal skin and inflamed skin differed from the distribution of the V beta families in the peripheral blood mononuclear cells (PBMC). Out of 71 CTCL cases, the clone was identified in 23 (32%).
We identified the following clones: 1 V beta 3.1 (16MF), 7 V beta 5.1 (1 CD8+ CTCL, 1 CTCL not classified, 1 MF, 1 PA, 3 SS), 1 V beta 6.7 (1 SS), 7 V beta 8.1/8.2 (2 CTCL not classified, 1 PLEO, 2 MF, 2 SS), 1 V beta 12.1 (1 PLEO), 3 V beta 17.1 (2 CTCL not classified, 1 MF), 2 V beta 22.1 (1 CTCL not classified, 1 MF), 1 TCR delta (SS). The frequency of the malignant clone V beta usage corresponded well to the repertoire of V beta in eczematous skin but not to the repertoire in PBMC.
In 6 patients, the malignant clone was mainly localized in the epidermis. In 17 cases, the clone-specific cells were distributed in epidermis and dermis equally. A retrospective analysis showed that preferential epidermal homing of the clone was associated with a non-aggressive clinical course. The V beta usage of CTCL and eczema suggests a special cutaneous microenvironment which might be co-created by certain (bacterial?) superantigens. A preferential epidermal homing of the clone might have prognostic implications.
Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion.
Jackow CM, Cather JC, Hearne V, Asano AT, Musser JM, Duvic M.
Department of Dermatology, University of Texas Medical School, Houston, USA.
Blood 1997 Jan 1;89(1):32-40 Abstract quote
Forty-two patients with cutaneous T-cell lymphoma, including 31 with exfoliative erythroderma or Sezary syndrome and 11 with mycosis fungoides, were studied for the occurrence of staphylococcal infection.
Thirty-two of 42 (76%) had a positive staphylococcal culture from skin or blood. One half of the patients with positive cultures grew Staphylococcus aureus. This group included 11 with Sezary syndrome and 5 with rapidly enlarging mycosis fungoides plaques or tumors. All of the S aureus carried enterotoxin genes. Surprisingly, 6 of 16 strains were the same toxic shock toxin-1 (TSST-1)-positive clone, designated electrophoretic type (ET)-41. Analysis of the T-cell receptor V beta repertoire in 14 CTCL patients found that only 4 had the expected monoclonal expansion of a specific V beta gene, whereas 10 had oligoclonal or polyclonal expansion of several V beta families. All patients with TSST-1+ S aureus had overexpansion of V beta Z in blood and/or skin lesions.
These studies show that S aureus containing superantigen enterotoxins are commonly found in patients with CTCL especially individuals with erythroderma where they could exacerbate and/or perpetuate stimulate chronic T-cell expansion and cutaneous inflammation. Attention to toxigenic S aureus in CTCL patients would be expected to improve the quality of care and outcome of this patient population.
GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION GENERAL
Practical evaluation and management of cutaneous lymphoma
Maxwell A. Fung, MD
Michael J. Murphy, MD
Diane M. Hoss, MD
Jane M. Grant-Kels, MD
J Am Acad Dermatol 2002;46:325-57 Abstract quote
Accurate evaluation of patients with suspected or known cutaneous lymphoma requires the integration of many sources and types of information, including clinical evaluation, microscopic analysis of tissue, immunophenotyping, gene rearrangement studies, clinical staging, and longitudinal observation. Diagnoses should be based on knowledge of specific lymphoma types as described in modern classification systems.
Management of patients with cutaneous lymphoma requires collaboration among dermatologists, dermatopathologists, hematopathologists, and medical, surgical and radiation oncologists.
European Organization for Research and Treatment of Cancer (EORTC) Classification of Primary Cutaneous Lymphomas Primary Cutaneous T cell Lymphoma (CTCL) Indolent MF
MF + follicular mucinosis
CTCL-Large Cell CD30+ Anaplastic
CTCL-Aggressive Sezary Syndrome
Large cell, CD30
Large cell, CD30
CTCL-Provisional Granulomatous slack skin
Pleomorphic small/medium sized
Subcutaneous panniculitis-like T cell lymphoma
Primary Cutaneous B cell Lymphoma (CBCL)
CBCL-Indolent Follicle center cell lymphoma
Immunocytoma (Marginal zone B-cell lymphoma)
CBCL-Intermediate Large B-cell lymphoma of the leg CBCL-Provisional Intravascular large B-cell lymphoma
T-Cell Rich B-Cell Lymphoma
HISTOPATHOLOGICAL VARIANTS CHARACTERIZATION CD4- CD80 CTCL CD4 CD8 `Double-Negative' Cutaneous T-Cell Lymphomas Share Common Histologic Features and an Aggressive Clinical Course
Dan Jones, M.D. , Ph.D. ; Francisco Vega, M.D. , Ph.D. ; Andreas H. Sarris, M.D. , Ph.D. ; L. Jeffrey Medeiros, M.D.
From the Division of Pathology and Laboratory Medicine (D.J., F.V., L.J.M.) and the Department of Lymphoma (A.H.S.), University of TexasM.D. Anderson Cancer Center, Houston, Texas, U.S.A.
Am J Surg Pathol 2002;26:225-231 Abstract quote
We report 15 patients with CD4CD8 double-negative T-cell lymphoma arising in skin.
There were seven women and eight men with a mean age at diagnosis of 53 years (range 1977 years). All but two patients presented with solitary or multiple cutaneous nodule(s). Initial and recurrent biopsy specimens showed a dense infiltrate centered in the mid-dermis (extending into subcutis when sampled) of small to intermediate-sized lymphocytes with indistinct nucleoli and frequently irregular nuclear contours. Periadnexal infiltration and epidermal ulceration were present in five cases with the intraepidermal cells being primarily reactive CD4+ T cells. All cases were negative for CD30 and terminal deoxynucleotidyltransferase; one showed expression of CD56, and six of eight tested cases were positive for T-cell receptor- expression.
Despite systemic chemotherapy, all 12 patients with clinical follow-up showed recurrent or progressive disease with widespread cutaneous dissemination in 10 of 12. Eventual dissemination to lymph nodes or bone marrow occurred in two patients each, with at least nine patients dead of disease or treatment complications. Only two patients achieved lasting clinical remission (with 2´-deoxycoformycin/pentostatin and nelarabine, respectively).
CD4CD8 double-negative CTCL has distinctive histologic features and cytomorphology with a marked propensity for rapid multifocal cutaneous dissemination.
CD8+ Junctional CD8+ Cutaneous Lymphomas With Nonaggressive Clinical Behavior
A CD8+ Variant of Mycosis Fungoides?
Reinhard Dummer, MD; Jivko Kamarashev, MD; Werner Kempf, MD; Andreas C. Häffner, MD; Monika Hess-Schmid, MD; Günter Burg, MD
Arch Dermatol. 2002;138:199-203 Abstract quote
To evaluate the clinical and prognostic features in primary cutaneous CD8+ T-cell lymphomas, which are rare and considered to be aggressive cutaneous lymphoproliferative disorders.
Single-center retrospective study.
Lymphoma clinic (referral center) of a university hospital.
Three patients presented with CD8+ cutaneous lymphoma characterized by a patchlike pattern and hyperpigmentation.
Histological analysis revealed a CD3+, CD8+ small-cell infiltrate showing a remarkable affinity to the dermoepidermal junction zone. Clonality for the T-cell receptor chain was detected by polymerase chain reaction followed by denaturing gradient gel electrophoresis. The clinical presentation lasted several years (6 and 9 years, respectively) before the correct diagnosis was made. Treatment with nontoxic approaches (UV-B and local steroids) was successful. Aggressive clinical behavior was not observed.
Our 3 cases of junctional CD8+ cutaneous T-cell lymphomas were characterized by hyperpigmentation and nonaggressive clinical behavior. This type of lymphoma, which can be considered a CD8+ mycosis fungoides variant, must be distinguished from other types of cutaneous CD8+ lymphomas so that overtreatment can be avoided.
Localized cutaneous small to medium-sized pleomorphic T-cell lymphoma: A report of 3 cases stable for years.
von Den Driesch P, Coors EA.
Department of Dermatology, University of Erlangen-Nuremberg.
J Am Acad Dermatol 2002 Apr;46(4):531-5 Abstract quote
Small to medium-sized pleomorphic cutaneous T-cell lymphomas represent a provisional entity in the new European Organization for Research and Treatment of Cancer classification.
We describe 3 patients with a localized and outstanding stable variant of this tumor. A median follow-up period of 50 months did not reveal any spread into regional lymph nodes or to distant sites in any patient.
Weedon D. Weedon's Skin Pathology. Churchill Livingstone. 1997.
SALT-Skin-associated lymphoid tissue. Broad term used to describe native B lymphocytes within the skin. It is theorized that these lymphocytes may give rise to some CBCLs.
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