 |
|
|
|
|
|
|
|
|
 |
 |
 |
 |
 |
 |
 |
 |
|
Background
This is the most common skin lymphoma and is a distinct form of cutaneous T cell lymphomas. It is rare, with about 1 new case per 1 million in the United States. Males in their mid to late adulthood are favored. There is a propensity for lesions to occur on the lower trunk, thighs, and breasts in women. In later stages of the disease, dissemination is common.
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.
Immunohistochemistry and molecular genetics have revealed aberrant expression of the usual surface antigens of the T lympocytes. Most cases of MF are neoplastic T helper cells which are CD4 positive. These show gene rearrangements of the T cell receptors, usually of the alpha/beta receptors, but occasionally of the gamma/delta receptors. What causes MF is still unknown although a viral etiology is still hotly debated.
The pathologist is often faced with making the diagnosis of the early patch stage. If the classic histologic features are present associated with characteristic clinical features, the diagnosis can usually be made. The more usual scenario are a few atypical lymphocytes in a patient with a chronic rash. The clinical diagnosis is given as "Rule out MF". In these instances, a diagnosis of an atypical lymphocytic infiltrate, suspicious for MF is sometimes made. Molecular analysis looking for rearrangement of the T cell receptors can be done but the yield of these studies is directly related to the number of atypical lymphocytes. Unfortunately, in the patch stage of the disease, the stage most likely to prompt such a study, there are few lymphocytes yielding equivocal results. Frequently, sequential follow-up biopsies are needed to establish a diagnosis.
OUTLINE
Epidemiology Disease Associations Acquired ichthyosis
Hodgkin's disease
Melanocytic Nevus
Nail dystrophy
UrticariaPathogenesis Apoptosis and CD95 (Fas)
Apoptosis and Galectin-1
Chromosomal abnormalities
Epstein-Barr Virus
Interleukins
NK-kappa B
T-cell Chemokine ReceptorLaboratory/Radiologic/
Other Diagnostic TestingTARC/CCL17 (Chemokine) Gross Appearance and Clinical Variants Acanthosis-nigricans
Histopathological Features and Variants Special Stains/
Immunohistochemistry/
Electron MicroscopyDifferential Diagnosis Prognosis and Treatment Commonly Used Terms Internet Links
DISEASE ASSOCIATIONS CHARACTERIZATION ACQUIRED ICHTHYOSIS HODGKIN'S DISEASE Semin Diagn Pathol 1992; 9: 297–303.
J Cutan Pathol 1999; 26: 311–4
N Engl J Med 1992; 326: 1115–22.
J Clin Pathol 1996; 49: 504–7
Cancer 1979; 44: 1408–13
Arch Pathol Lab Med 1986; 110: 1029–34
Cancer 1984; 53: 463–7
The two neoplasms can occur simultaneously, or the diagnosis of HL can precede or follow a diagnosis of NHLAmong peripheral T-NHL, mycosis fungoides (MF) is the neoplasm most commonly associated with HL
Some authors have found MF and HL derived from the same clone demonstrated a common single T-cell clone for lymphomatoid papulosis, MF, and HL occurring in the same patient
Other authors have not found evidence for a common clonal origin of MF associated with HL
Mod Pathol 2001;14:91-97 (Quoted from abstract)
Case report:
Patient with a history of MF in Clinical Stage 1A who developed retroperitoneal lymphadenopathy 9 years after the initial diagnosis of MF. A bone marrow biopsy obtained at this time showed nodular involvement by a mixed cellular infiltrate with large, atypical cells consistent with Hodgkin and Reed-Sternberg (RS) cells. These atypical cells were positive for CD30 and CD15 and did not express B- or T-cell markers. In addition, they lacked evidence of infection by Epstein-Barr virus, both by immunohistochemical staining for latent membrane protein 1 and by in situ hybridization for EBER1/2. The background population consisted mainly of small T cells without morphological or phenotypical signs of malignancy. Review of the skin biopsy obtained 9 years before showed the typical features of MF. Polymerase chain reaction analysis of the T-cell receptor -gene confirmed the presence of a clonal T-cell rearrangement in the skin specimen. The bone marrow biopsy, however, showed a polyclonal pattern both for the T-cell receptor -gene, as well as for immunoglobulin heavy chain genes. Isolation of RS cells stained for CD30 was performed by laser capture microdissection. Polymerase chain reaction analysis of several groups of RS cells showed a reproducible biallelic rearrangement of IgH genes, which was confirmed by cloning and sequencing of polymerase chain reaction products.Conclusion:
First case in which a distinct clonal origin of MF and Hodgkin’s lymphoma arising in the same patient is clearly demonstrated, based on molecular analysis of microdissected RS cells.LYMPHOMA, SYSTEMIC
Author Affiliations: Departments of Dermatology.
OBJECTIVE: To assess risks for developing second malignancies in patients with mycosis fungoides or Sezary syndrome.
DESIGN: Retrospective study of 2 cohorts.
SETTING: Nine population-based US cancer registries that constitute the Surveillance, Epidemiology, and End Results Program (SEER-9), and Stanford University referral center cohort of patients with cutaneous lymphoma. Patients Patients with mycosis fungoides or Sezary syndrome from the SEER-9 registry diagnosed and followed up from 1984 through 2001 and from the Stanford University cohort diagnosed and followed up from 1973 through 2001.
MAIN OUTCOME MEASURES: Relative risk was estimated using the standardized incidence ratio (SIR). The expected cancer incidence for both cohorts was calculated using age-, sex-, race-, and calendar year-specific SEER-9 incidence rates for the general population. Nonmelanoma skin cancers were excluded because these cancers are not routinely reported by the SEER database.
RESULTS: In the SEER-9 cohort (n = 1798), there were 197 second instances of cancer (SIR = 1.32; 95% confidence interval [CI], 1.15-1.52) at all sites. Significantly elevated risk (P<.01) was observed for Hodgkin disease (6 cases; SIR = 17.14; 95% CI, 6.25-37.26) and non-Hodgkin lymphoma (27 cases; SIR = 5.08; 95% CI, 3.34-7.38). Elevated risk (P<.05) was also observed for melanoma (10 cases; SIR = 2.60; 95% CI, 1.25-4.79), and urinary cancer (21 cases; SIR = 1.74; 95% CI, 1.08-2.66). In the Stanford University cohort (n = 429), there were 37 second instances of cancer (SIR = 1.04; 95% CI, 0.76-1.44). Elevated risk (P<.01) was observed for Hodgkin disease (3 cases; SIR = 27.27; 95% CI, 5.35-77.54). Elevated risk (P<.05) was also observed for biliary cancer (2 cases; SIR = 11.76; 95% CI, 1.51-42.02).
Conclusion Updated SEER (population based) and Stanford (clinic based) data confirm the generalizability of earlier findings of increased risk of lymphoma in patients with mycosis fungoides or Sezary syndrome.MELANOCYTIC NEVUS
Histologic features of melanocytic nevi seen in association with mycosis fungoides
Jennifer M. McNiff and Earl J. Glusac
J Cutan Pathol 2003;30:606-610 Abstract quote
Background: Many different tumors have been reported to occur simultaneously as collision lesions. To date, no such events have been reported between mycosis fungoides (MFs) and melanocytic neoplasms.Methods: Two cases are presented in which patches of MF were superimposed on melanocytic nevi. In addition, 967 biopsies of MF from 411 patients were identified in an 8-year retrospective database search. Patient pathology history summaries were reviewed to identify inflamed nevi, atypical nevi, and melanoma submitted for histologic evaluation from this population.
Results: The occurrence of MF in a congenital nevus was associated with a halo phenomenon restricted to the affected region of the nevus in one patient. In the other patient, nests of two morphologies (lymphocytic and melanocytic) in the same biopsy presented a potentially confusing histologic picture. No other cases of MF superimposed on a nevus were identified in 967 biopsies from 411 patients with a histological diagnosis of MF seen over the past 8 years. In this population, 57 biopsies of melanocytic lesions were identified from 28 patients, including three atypical nevi and three melanomas.
Conclusions: The presence of MF superimposed on a nevus is rare and may lead to confounding histologic features or the development of a halo nevus phenomenon.
NAIL DYSTROPHY URTICARIA, COLD
Cold urticaria in a patient with mycosis fungoides.Koay J, Jones D, Duvic M.
Baylor College of Medicine, Houston, Texas 77030, USA.
J Am Acad Dermatol 2002 Oct;47(4):608-10 Abstract quote We report what we believe to be the first documentation of a patient with both cold urticaria and mycosis fungoides. The patient described a marked worsening of his long-standing lesions of mycosis fungoides at the same time as the onset of cold sensitivity.
We believe this suggests a possible association between these 2 rare diseases.
PATHOGENESIS CHARACTERIZATION GENERAL Compr Ther 1998;24:117-122
CD8 T cells respond to antigens processed and presented to the class I MHC proteins
Once presented, the cytoplasmic proteins are processed into smaller peptides and transported into the endoplasmic reticulum linking up to a class I MHC molecule where it is transported to the antigen presenting cell (APC) surface for interaction with a CD8 cell
CD4 T-cells respond to antigens presented to the class II MCH pathway which processes exogenous peptides and cell surface proteins
CD4 cells differentiate into Th1 and Th2 subgroups
Th1 produce IFN-gamma and TNF-alpha
Th2 produce IL4, 5, 6, 9, 10, and 13 and induce strong Ab responses and eosinophil accumulationIn CTCL, the normal balance of T-cells reverses and CD4>CD8 and Th2 dominate Th1
Keratinocytes also express ICAM-I and class II molecules
Endothelial cells attract T-cells via increased E-selectinAPOPTOSIS AND CD95 (FAS)
Expression of Fas and Fas-ligand in primary cutaneous T-cell lymphoma (CTCL): association between lack of Fas expression and aggressive types of CTCL.Zoi-Toli O, Vermeer MH, De Vries E, Van Beek P, Meijer CJ, Willemze R.
Department of Dermatology, Free University Hospital, PO Box 7057, 1007 MB Amsterdam, the Netherlands.
Br J Dermatol 2000 Aug;143(2):313-9 Abstract quote BACKGROUND: Fas (CD95; APO-1) is a transmembrane protein that mediates apoptosis upon cross-linking with Fas-ligand (Fas-L). Interaction of Fas-L expressed by cytotoxic T cells with Fas-expressing tumour cells plays an important part in antitumour immune responses.
OBJECTIVES: We aimed to investigate Fas and Fas-L expression in frozen and paraffin-embedded material from a large group of patients with cutaneous T-cell lymphoma (CTCL).
METHODS: Immunostaining with monoclonal antibodies against Fas and Fas-L was performed in material from 23 patients with mycosis fungoides (MF), 10 with lymphomatoid papulosis (LyP), 10 with CD30-positive primary cutaneous large T-cell lymphoma (LTCL) and nine with CD30-negative LTCL. The results were correlated with the type and stage of CTCL and clinical features.
RESULTS: Expression of Fas by the large majority of the neoplastic T cells was observed in 15 of 15 cases of plaque-stage MF, 10 of 10 cases of LyP and 10 of 10 cases of CD30-positive LTCL, but only in four of 12 cases of tumour-stage MF and two of nine cases of CD30-negative LTCL. In three of four MF patients in whom both plaques and tumours could be studied, a significant decrease in Fas expression was observed with progression from plaque-stage to tumour-stage disease. Fas-L was expressed by > 50% of the neoplastic T cells in 46 of 56 biopsies, and no clear relationship with type of CTCL and clinical behaviour was observed.
CONCLUSIONS: This study demonstrates loss of Fas expression in aggressive types of CTCL, but not in indolent types of CTCL. These data suggest that loss of Fas receptor expression may be one of the mechanisms that allow tumour cells to escape an effective immune response, and may contribute to the unfavourable prognosis of some types of CTCL.
Osella-Abate S, Zaccagna A, Savoia P, Quaglino P, Salomone B, Bernengo MG.
Department of Medical and Surgical Specialties, 1st Dermatologic Clinic, University of Torino.
J Am Acad Dermatol 2001 Jan;44(1):40-7 Abstract quote
The mechanisms of extracorporeal photochemotherapy (ExP) therapeutic activity in cutaneous T-cell lymphomas (CTCLs) are not yet well understood, even though it has been suggested that a major mechanism may be induction of apoptosis. In vitro studies demonstrate that UVA-induced apoptosis is mediated by CD95-Fas expression and inhibited by Bcl-2 up-regulation and that UVA irradiation is able to down-regulate Bcl-2 expression.
High-resolution multiparameter flow-cytometric analyses were used to evaluate Bcl-2/CD95-Fas expression on phenotypically identifiable circulating clonal T cells from 7 patients with CTCL (4 with Sezary syndrome and 3 with mycosis fungoides with peripheral involvement) before and during ExP, in an attempt to ascertain whether Bcl-2/CD95-Fas status can be related to the hematologic response. A Bcl-2 normal phenotype before ExP or a normalization in Bcl-2 expression during ExP were related to a better clinical response, whereas a persistent Bcl-2 high expression was a negative prognostic factor. On the other hand, no response was found in patients with a CD95-Fas-negative phenotype, whereas the expression of CD95-Fas was associated with hematologic remission.
Although further studies are needed to confirm these preliminary results, this study suggests that Bcl-2 and CD95-Fas expression could be evaluated, together with the other known clinical and immunologic factors, as additional parameters related to clinical response in patients with CTCL undergoing ExP.
Proapoptotic and antiapoptotic markers in cutaneous T-cell lymphoma skin infiltrates and lymphomatoid papulosis.Nevala H, Karenko L, Vakeva L, Ranki A.
Department of Dermatology and Venereal Diseases, Helsinki University Central Hospital, Finland.
Br J Dermatol 2001 Dec;145(6):928-37 Abstract quote BACKGROUND: In cutaneous T-cell lymphoma (CTCL) lesions, both reactive T cells and malignant T cells intermingle. The disease progression is mostly slow. Recent evidence suggests that even if clinical remission is reached, malignant cells persist and a relapse follows sooner or later. To wha extent tumour cell apoptosis occurs in the skin lesions either due to the reactive T cells or t therapeutic efforts is not known.
OBJECTIVES: To determine the extent of tumour cell apoptosis and the expression of proapoptotic an antiapoptotic markers in serial skin lesion samples from patients with CTCL, and to compare th findings with those in patients with lymphomatoid papulosis (LyP).
METHODS: Thirty-four skin samples were obtained from 12 patients with CTCL at the time o diagnosis and at a mean of 1.6, 3 and 6 years later. The patients received psoralen plus ultraviolet (PUVA), electron beam or cytostatic treatments. In addition, fresh post-treatment samples fro three patients with CTCL undergoing PUVA therapy were obtained. For comparison, skin biopsies o five patients with LyP were studied. Immunohistochemical demonstration of the expression of th following markers was performed on formalin-fixed skin sections: Fas (CD95), Fas ligand (FasL) bcl-2, granzyme B, the tumour-suppressor protein PTEN and the effector caspase, caspase-3. Th malignant cells were identified morphologically, and apoptotic cells were identified with th terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling method on parallel sections.
RESULTS: In untreated CTCL lesions, apoptotic lymphocytes were extremely rare, and no increase in the number of apoptotic cells was observed after any of the treatments used. In LyP, apoptotic cell were more frequent, comprising on average 5% of the infiltrate. The apoptosis-associated marker Fas, FasL, caspase-3 and granzyme B were expressed by morphologically neoplastic cells in CTCL and by large atypical cells in LyP, with no significant differences. However, only a few reactive cell in CTCL infiltrates expressed granzyme B while about 10% of the corresponding cells were positive in LyP. The expression of antiapoptotic bcl-2 was more frequent in CTCL than in LyP, while PTE expression was high in both instances. The number of bcl-2 + cells tended to decrease after therapy When comparing the findings between the first and the last samples, a decrease in the number of bcl-2+ cells and an increase in Fas+ cells was associated with disease progression, despite therapy, while the opposite was true for remissions.
CONCLUSIONS: Apoptosis was found to be a rare event in CTCL lesions irrespective of preceding therapy During patient follow-up, no significant differences in the expression of apoptotic marker was observed while in most cases a lower level of antiapoptotic bcl-2 expression was observed after all types of therapies and in association with disease progression when compared with high expression in the untreated lesions. The absence of apoptosis and high expression of bcl-2 together with a low expression of apoptosis-inducing granzyme B in the reactive lymphocytes in CTCL could explain the chronic nature of the disease and the poor response to therapy, while the more frequent occurrence of granzyme B and apoptosis together with a lower level of expression of bcl-2 by the large atypical cells in LyP could contribute to the favourable outcome of the latter.
APOPTOSIS AND GALECTIN-1
Galectin-1-mediated apoptosis in mycosis fungoides: the roles of CD7 and cell surface glycosylation.Roberts AA, Amano M, Felten C, Galvan M, Sulur G, Pinter-Brown L, Dobbeling U, Burg G, Said J, Baum LG.
Department of Pathology, UCLA School of Medicine, Los Angeles, California 90095-0657, USA.
Mod Pathol. 2003 Jun;16(6):543-51. Abstract quote Sezary cells, the malignant T cells in mycosis fungoides/Sezary syndrome, resist a variety of apoptosis-inducing agents, a feature that contributes to the poor response to therapy in mycosis fungoides.
Galectin-1 is a mammalian lectin that triggers T cell apoptosis. For T cells to be susceptible to galectin-1-induced apoptosis, the T cells must express specific glycoprotein receptors, such as CD7, that bear the specific oligosaccharides recognized by galectin-1. Because Sezary cells are characteristically CD7(-), lack of CD7 expression has been proposed to render Sezary cells resistant to galectin-1-induced death. However, the role played by aberrant cell surface glycosylation in resistance of Sezary cells to galectin-1 has not been examined.
In this study, we demonstrated abundant galectin-1 in mycosis fungoides skin lesions, indicating that Sezary cells are exposed to galectin-1 in vivo. To determine specific characteristics of Sezary cells that contribute to galectin-1 resistance, we assessed CD7 expression and cell surface glycosylation of Sezary cells in mycosis fungoides lesions and of four Sezary T cell lines. Sezary cells in primary lesions and Sezary T cell lines demonstrated a characteristic "glycotype" with sialylated core 1 O-glycans that promote galectin-1 resistance. Expression of CD7 was necessary but not sufficient for galectin-1-induced death of Sezary cell lines. In addition, CD7(-) Sezary cell lines, and Sezary cells within mycosis fungoides lesions, expressed galectin-1, whereas CD7-positive Sezary cell lines did not express galectin-1.
We propose that both loss of CD7 expression and altered cellular glycosylation contribute to apoptosis resistance of malignant T cells in mycosis fungoides.CHROMOSOMAL ABNORMALITIES Cytogenetic findings in peripheral T-cell lymphomas as a basis for distinguishing low-grade and high-grade lymphomas.
Schlegelberger B, Himmler A, Godde E, Grote W, Feller AC, Lennert K.
Department of Human Genetics, University of Kiel, Germany.
Blood 1994 Jan 15;83(2):505-11 Abstract quote
Cytogenetic studies on lymph node and skin biopsy specimens and peripheral blood in 104 patients with peripheral T-cell lymphomas (PTL) were compared with histopathologic diagnoses made according to the updated Kiel classification. Low-grade lymphomas presented normal metaphases more frequently than high-grade ones (P < .0001).
This difference remained significant if cases with greater than 10% and greater than 50% normal metaphases in unstimulated cultures and in cultures stimulated by different mitogens were compared. On the other hand, high-grade lymphomas more often showed aberrant clones (P < .05), triploid to tetraploid clones (P < .0001), and complex clones with more than four chromosome changes (P < .01). Low-grade PTL showed consistent cytogenetic features.
Clones with both inv(14)(q11q32.1) and trisomy 8q, mostly caused by i(8q)(q10), were found in all cases of T-cell chronic lymphocytic leukemia (T-CLL) and T-cell prolymphocytic leukemia (T-PLL). Trisomy 3 was observed only in angioimmunoblastic lymphadenopathy with dysproteinemia (AILD)-type PTL, T-zone lymphoma, and lymphoepithelioid lymphoma. Moreover, the proportion of normal metaphases in these PTL was higher than in the other low-grade PTL (P < .01). On the contrary, T-CLL, T-PLL, and cutaneous T-cell lymphomas (CTCL) showed complex clones (P < .0001), duplications in 6p (P < .01), deletions in 6q (P < .01), trisomy 8q (P < .00001), inv(14) (P < .00001), and monosomy 13 or changes of 13q14 (P < .001) more frequently than the other low-grade PTL. Trisomy 5 and + X predominated in AILD-type PTL. A cytogenetic feature characteristic of AILD-type PTL and CTCL was unrelated clones, which were found in 15% of AILD-type PTL and 17% of CTCL.
The only chromosome aberration restricted to a certain high-grade PTL was t(2;5)(p23;q35) in large-cell anaplastic lymphoma. Deletions in 6q, total or partial trisomies of 7q, and monosomy 13 or changes of 13q14 turned out to be significantly more frequent in high-grade than in low-grade lymphomas (P < .01, P < .01, and P < .05, respectively). In summary, the cytogenetic findings in our series of 104 PTL enabled us to distinguish not only between low-grade and high-grade lymphomas but also between various entities of PTL.
Thus, the cytogenetic findings paralleled the histopathologic diagnoses made according to the updated Kiel classification.
EPSTEIN-BARR VIRUS Detection of Epstein-Barr virus and human herpesvirus 7 and 8 genomes in primary cutaneous T- and B-cell lymphomas.
Nagore E, Ledesma E, Collado C, Oliver V, Perez-Perez A, Aliaga A.
Department of Dermatology, Hospital General Universitario, C/Denia 20-6(a), 46006 Valencia, Spain.
Br J Dermatol 2000 Aug;143(2):320-3 Abstract quote
BACKGROUND: Several studies have investigated the possible involvement of viral agents, particularly herpesviruses, in primary cutaneous lymphoma (PCL).
OBJECTIVES: Our aim was to screen for the presence of human herpesvirus 7 (HHV-7) and 8 (HHV-8) genomes in samples of PCL, and to determine if their presence was independent of Epstein-Barr virus (EBV).
METHODS: Screening was performed using polymerase chain reaction assay in 64 skin samples from historical lesional tissues with PCL. RESULTS: Only nine cases showed positivity for HHV-7: four of 29 mycosis fungoides (MF), two of four CD30-positive large-cell cutaneous T-cell lymphoma (CTCL), two of 12 follicle centre cutaneous B-cell lymphoma (CBCL) and one of nine marginal zone CBCL. Fifteen cases tested positive for EBV: seven of 29 MF, two of four pleomorphic small/medium sized CTCL, three of three angiocentric CTCL, one of 12 follicle centre CBCL and two of nine marginal zone CBCL. All cases were uniformly negative for HHV-8. No simultaneous positivity was found for EBV and HHV-7. Controls tested negative for all viruses.
CONCLUSIONS: The findings indicate that EBV, HHV-7 and HHV-8 seem not to be involved in the pathogenesis of PCL.
INTERLEUKINS Increased interleukin 5 production in eosinophilic Sezary syndrome J Am Acad Dermatol 2001;44:28-32
Marked increased IL-5 by peripheral blood mononuclear cells
This was reduced after exposure to IFN-alpha or IL-12LOSS OF HETEROZYGOSITY
*Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN †US Labs, Irvine, CA ‡Departments of Pathology and Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR.
Mycosis fungoides (MF) exhibits a variety of underlying molecular defects. Loss of heterozygosity (LOH) is a technique used to detect chromosomal imbalances in neoplastic disorders using archival tissue.
We analyzed skin biopsies of MF in different stages for the presence of LOH at specific loci to evaluate underlying genetic aberrations involved in MF and its progression. Twenty-five skin biopsies (15 plaque stage and 10 tumor stage) from 19 patients were evaluated. LOH was examined at 1p22 (D1S2766), 9p21 [IFNA, p15 (D9S1748), p16 (D9S171)], 10q23 [PTEN (D10S185, D10S541, D10S2491)], and 17p13 [p53 (TP53)]. Abnormal lymphocytes were microdissected from formalin-fixed, paraffin-embedded tissue sections. Sixteen of the 25 (64%) specimens evaluated had at least one abnormal LOH locus and LOH was identified in 7 of 15 (47%) plaque and in 9 of 10 (90%) tumor stage lesions, respectively. All 3 patients with sequential biopsies (plaque followed by tumor lesions) had additional LOH abnormalities in tumor specimens compared with plaque stage lesions.
LOH most frequently involved chromosome 10, including 7 of 10 (70%) tumor stage lesions. Loss of multiple alleles was only identified in tumor stage cases, with 3 tumors undergoing allelic losses at 3 separate loci.
Our results suggest that LOH studies are a robust method for evaluating genetic abnormalities in MF. Tumor stage lesions manifest increasing allelic losses compared with plaque stage. Further, in this series, several loci associated with the tumor suppressor gene PTEN on chromosome 10 appear to be associated with progression from plaque to tumor stage.NK-KAPPA B Hum Pathol 2000:31:1482-1490
Immunoperoxidase study of 23 cutaneous lesions and single lymph node biopsyNeoplastic T lymphocytes from 22/24 cases showed strong cytoplasmic expresion of active p65(Rel A)
Significant increase in apoptosis, decrease in NF-kappaB DNA binding activity, marked decrease in nuclear p65 expresion were seen after chemical NF-kappaB inhibitionT-CELL CHEMOKINE RECEPTOR The T-Cell Chemokine Receptor CXCR3 Is Expressed Highly in Low-Grade Mycosis Fungoides
Di Lu etal.
Am J Clin Pathol 2001;115:413-421 (Abstract quote)
We examined the expression of the receptor for these chemokines, CXCR3, in cutaneous T-cell lymphoma. We compared CXCR3 expression with that of cutaneous lymphocyte antigen (CLA) and the activation marker CD30. CXCR3 was expressed by at least a subset of tumor lymphocytes in all 25 cases of low-grade mycosis fungoides (MF), with most cells positive in 20 cases. In progressed or transformed MF, CXCR3 expression was noted in 5 of 22 cases. In 4 of 5 MF cases with sequential biopsy specimens, large cell transformation was accompanied by loss of CXCR3 expression. In contrast, CLA was expressed in 35 of 42 MF cases with no significant differences in expression level between low-grade and transformed cases. In other lymphomas, CXCR3 was expressed in 4 of 4 cases of lymphomatoid papulosis, 3 of 4 cases of CD8+ cutaneous T-cell lymphoma, and 3 of 6 cases of systemic T-cell lymphoma in skin, but not in 10 cases of cutaneous anaplastic large cell lymphoma.
CXCR3 expression was associated with epidermotropic T-cell tumors but was largely absent in dermal-based tumors. This phenotypic change likely influences the loss of epidermal localization.
The clonotypic T cell receptor is a source of tumor-associated antigens in cutaneous T cell lymphoma.
Berger CL, Longley J, Hanlon D, Girardi M, Edelson R.
Department of Dermatology, Yale University, School of Medicine, New Haven, Connecticut 06520, USA.
Ann N Y Acad Sci 2001 Sep;941:106-22 Abstract quote
To develop cancer vaccines for the treatment of cutaneous T cell lymphoma (CTCL), immunogenic peptides were identified by two approaches. First, through the use of "reverse immunology" the peptide sequence of the idiotypic region of the beta chain of the T cell receptor (TCR) was determined and a series of overlapping peptides synthesized and tested for CD8 T cell recognition.
In two patients, the idiotypic CDR3 region provided immunogenic epitopes that were recognized in a class I-restricted fashion by autologous CD8 T cell lines. In a second strategy, peptides were isolated directly from class I MHC molecules on the CTCL surface and sequenced. A peptide with partial homology to sequences contained in the conserved variable portion of the clonotypic TCR beta chain was recognized as immunogenic by autologous CD8 T cells. Therefore, both approaches demonstrated that the clonotypic TCR in CTCL is a source of immunogenic tumor epitopes. To confirm that recognition of TCR-derived sequences provides immunoprotection against tumor growth, a murine model of T cell lymphoma was studied. The immunogenicity of a thymoma, which lacks cell surface TCR expression, was enhanced by transfection of the beta chain of the TCR.
The studies reviewed in this paper demonstrate that the TCR can serve as one source for immunogenic tumor peptides in T cell lymphoma in vitro and in vivo. Presentation of TCR epitopes on dendritic cells that express high levels of MHC, costimulatory, and adhesion molecules may provide an effective means for immunization against T cell malignancy.
LABORATORY/
RADIOLOGICCHARACTERIZATION FLOW CYTOMETRY
Department of Dermatology, Ireland Cancer Center of University Hospitals of Cleveland/Case Western Reserve University, Cleveland, Ohio 44106, USA.
BACKGROUND: The pathologic evaluation of mycosis fungoides (MF) is a challenging area in dermatopathology.
OBJECTIVE: We sought to determine the usefulness of flow cytometry for the diagnosis of MF from skin biopsy specimens.
METHODS: Skin biopsy specimens from 22 patients with a clinical suggestion for MF were evaluated by 4-color flow cytometry. The results were correlated with the International Society for Cutaneous Lymphoma (ISCL) MF diagnostic score and molecular studies for T-cell receptor gene rearrangement.
RESULTS: A T-cell abnormality by flow cytometry was identified in all 11 patients with diagnostic ISCL scores whereas the 7 patients with either subdiagnostic ISCL scores or reactive histology showed no phenotypic abnormality by flow cytometry. In all, 10 of 11 patients with diagnostic skin biopsy specimens for MF had T-cell receptor gene rearrangements by polymerase chain reaction. Gene rearrangements were not detected in the subdiagnostic group.
LIMITATIONS: Small study size was a limitation.
CONCLUSION: Flow cytometry of skin biopsy specimens is a sensitive method for detecting abnormalities in MF and should be considered part of the routine workup of patients with a clinical suggestion of MF.RADIOLOGIC Computed tomography in the evaluation of cutaneous T-cell lymphoma.
Howlett DC, Wong WL, Smith NP, Ayers AB.
Department of Radiology, St Thomas's Hospital, London, UK.
Eur J Radiol 1995 May;20(1):39-42 Abstract quote
The computed tomography (CT) scans performed in 28 patients with cutaneous T-cell lymphoma (CTCL) were reviewed.
Fifteen patients had clinically advanced cutaneous mycosis fungoides, six patients Sezary syndrome and seven variant CTCL. Of the 40 scans available 12 were normal, 15 indeterminate and 13 abnormal. Indeterminate and abnormal nodes showed a predilection for inguinal and axillary sites with a relative sparing of deep nodal regions. Visceral involvement was infrequent. In six patients CT detected abnormalities not obvious clinically and upstaged the disease.
CT should be performed as part of the initial staging and as a baseline for follow-up in patients with advanced mycosis fungoides, Sezary syndrome and variant CTCL.
GENE REARRANGEMENT
Department of Pathology, Stanford University, Stanford, California 94035, USA.
BACKGROUND: The diagnosis of mycosis fungoides (MF) is often difficult because of significant clinical and histopathologic overlap with inflammatory dermatoses. T-cell receptor (TCR)gamma chain rearrangement by polymerase chain reaction (PCR) (TCR-PCR) is a helpful adjuvant tool in this setting, but several of the inflammatory dermatoses in the differential diagnosis of MF may contain a clonal T-cell proliferation.
OBJECTIVE: We examined whether analysis for T-cell clonality and comparison of the clones with the standardized BIOMED-2 PCR multiplex primers for the TCRgamma chain from two anatomically distinct skin sites improves diagnostic accuracy.
METHODS: We examined two biopsy specimens each from 10 patients with unequivocal MF, from 18 patients with inflammatory dermatoses, and from 18 patients who could initially not be definitively given a diagnosis based on clinical and histopathologic criteria.
RESULTS: Eight of 10 patients with unequivocal MF had an identical clone in both biopsy specimens. Two of 18 patients with inflammatory dermatoses were found to have a clone in one of the biopsy specimens. On further follow-up of the 18 patients with morphologically nondiagnostic biopsy specimens, 13 of 18 were later confirmed to have MF and 5 of 18 had inflammatory dermatoses. Eleven of 13 patients with MF had an identical clone in both biopsy specimens; two of 13 had a polyclonal amplification pattern in both biopsy specimens. Four of 5 patients with inflammatory dermatoses had no clone in either biopsy specimen. One patient with an inflammatory dermatosis had an identical clone in both specimens. The sensitivity of TCR-PCR analysis to evaluate for an identical clone at different anatomic skin sites (dual TCR-PCR) is 82.6% and the specificity is 95.7%.
LIMITATIONS: The number of patients in the study group was limited.
CONCLUSION: These data suggest that dual TCR-PCR is a very promising technique with high specificity in distinguishing MF from inflammatory dermatoses.Analysis of T-Cell Receptor Gene Rearrangement for Predicting Clinical Outcome in Patients With Cutaneous T-Cell Lymphoma A Comparison of Southern Blot and Polymerase Chain Reaction Methods
Thaddeus Juarez, MD; Scott N. Isenhath, MD; Nayak L. Polissar, PhD; Daniel E. Sabath, MD, PhD; Brent Wood, MD, PhD; Deena Hanke, BS, MS; Claire L. Haycox, MD, PhD; Gary S. Wood, MD, PhD; John E. Olerud, MD
Arch Dermatol. 2005;141:1107-1113. Abstract quote Objective To extend previous observations regarding the prognostic value of analyzing lymph node DNA from patients with cutaneous T-cell lymphoma for the presence of a monoclonal T-cell population by Southern blot vs polymerase chain reaction (PCR) methods.
Design Inception cohort study from 1982 to 1998. Recruitment of new patients ended in 1994.
Setting A tertiary care referral center in Seattle, Wash.
Patients Fifty-five uniformly staged patients with the diagnosis of cutaneous T-cell lymphoma who underwent a lymph node biopsy, 21 with clinically abnormal nodes and 34 with normal nodes.
Interventions Lymph nodes were evaluated for T-cell receptor (TCR)
-chain gene rearrangement by 2 PCR methods: capillary electrophoresis and denaturing gradient gel electrophoresis. The same lymph nodes were evaluated by Southern blot analysis for TCR
-chain gene rearrangement and examined histopathologically on the basis of the National Cancer Institute lymph node classification system. Patients were observed clinically for a mean of9.5 years.
Main Outcome Measures Skin stage, clinical lymph node examination, lymph node histologic examination, Southern blot analysis, and PCR analyses were evaluated as potential prognostic predictors by univariate and multivariate analyses. The statistical association of TCR analysis and clinical outcome was determined among all patients. Hazard ratios (HRs) by Cox proportional hazards regression analysis were used to estimate the risk of a poor clinical outcome. Cumulative survival rates were analyzed by the Kaplan-Meier method.
Results A skin stage of T3 (tumors) or T4 (erythroderma) was the most powerful predictor of a poor clinical outcome (HR, 31.3 vs T1; P<.001). Patients with detectable TCR
Conclusions Detection of a monoclonal T-cell population by PCR in lymph nodes of patients with cutaneous T-cell lymphoma does not enhance prediction of clinical outcome and probability of survival beyond what can be determined from clinical examination and histologic lymph node scores. Skin stage and the presence or absence of lymphadenopathy remain the most important determinants of clinical outcome.
Improved sensitivity of T-cell clonality detection in mycosis fungoides by hand microdissection and heteroduplex analysis.
Dereure O, Levi E, Vonderheid EC, Kadin ME.
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
Arch Dermatol. 2003 Dec;139(12):1571-5. Abstract quote
BACKGROUND: The presence of a dominant T-cell clone is an important diagnostic criterion in cutaneous T-cell lymphomas (CTCLs) and in atypical T-cell cutaneous infiltrates. Procedures based on polymerase chain reaction (PCR) are the most sensitive to detect clonality, but heteroduplex analysis is less sensitive than other methods such as denaturing gradient gel electrophoresis.
OBJECTIVE: To assess whether a gross hand microdissection of the superficial (papillary) portion of the dermal infiltrate may improve the sensitivity of T-cell clonality detection by PCR-heteroduplex analysis in CTCL.
SETTING: Regional university hospital (secondary or tertiary referral center).Patients A total of 29 patients with a definite diagnosis of mycosis fungoides based on typical histologic and immunophenotypic features were selected with patch (16) or plaque (13) stages.
MAIN OUTCOME MEASURES: Assessment of T-cell clonality by PCR amplification of the T-cell receptor gamma chain followed by heteroduplex analysis using DNA extracted from the entire biopsy specimen and after gross microdissection of the subepidermal bandlike dermal infiltrate.
RESULTS: T-cell clonality was demonstrated in 24 of 29 cases when hand microdissection was used compared with 16 of 29 cases with DNA analysis from entire biopsy specimens; thus, hand microdissection resulted in a sensitivity improvement of approximatively 50%.
CONCLUSIONS: Hand microdissection substantially improves the detection of a T-cell clone in CTCL when using a PCR-heteroduplex analysis and could be used routinely in the clinical evaluation of T-cell infiltrates. Importantly, the microdissection method was found to be more useful for the detection of T-cell clones in early patch stages of CTCL than in plaque-stage disease.
Improved detection of clonality in cutaneous T-cell lymphomas using laser capture microdissection.
Yazdi AS, Medeiros LJ, Puchta U, Thaller E, Flaig MJ, Sander CA.
Department of Dermatology, Ludwig Maximilians University, Munich, Germany, and Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
J Cutan Pathol. 2003 Sep;30(8):486-91. Abstract quote
BACKGROUND: The diagnosis of cutaneous T-cell lymphoma is a challenge for both the pathologist and the clinician. This is particularly true for distinguishing early-stage mycosis fungoides from dermatitis. In this clinical setting, the presence of a clonal T-cell population supports lymphoma.
METHODS: Usually, routinely processed paraffin-embedded material is available for gene rearrangement analysis, and polymerase chain reaction (PCR)-based methods to assess clonality can be performed. One drawback of this approach is that sensitivity is suboptimal in biopsy specimens in which the lymphocytic infiltrate represents only a small percentage of all cells present. Another drawback is that DNA extraction from routinely processed, paraffin-embedded tissue is a time-consuming and labor-intensive procedure which can take up to 5 days in our laboratory. To bypass these problems, we used laser capture microdissection (LCM) to obtain lymphocytic infiltrates from tissue sections of formalin-fixed, paraffin-embedded skin biopsy specimens. This approach allows for more specific PCR assessment of the lymphocytic infiltrate and for rapid DNA extraction and PCR analysis.
RESULTS: Using the LCM approach, we could demonstrate clonal T-cell receptor gamma gene rearrangements in biopsy specimens that did not show clonality using DNA extracted by conventional methods from full tissue sections. In addition, DNA extraction and PCR analysis can be performed in 11 h.
CONCLUSION: In conclusion, applying LCM to clonality analysis of cutaneous lymphocytic infiltrates is rapid and more sensitive than conventional methods, and we recommend introducing this approach into the routine diagnostic setting.
Long-term implications of T-cell receptor gene rearrangement analysis by Southern blot in patients with cutaneous T-cell lymphoma.Guitart J, Camisa C, Ehrlich M, Bergfeld WF.
Departments of Dermatology at Northwestern University Medical Center and Cleveland Clinic Foundation.
J Am Acad Dermatol 2003 May;48(5):775-9 Abstract quote BACKGROUND: T-cell clonality analysis by Southern blot (TSB) in skin biopsy specimens suggestive of mycosis fungoides may be helpful in confirming the diagnosis of a cutaneous lymphoma. However, there are no data available regarding the long-term prognostic implication of such results.
OBJECTIVES: We sought to determine the long-term prognostic significance of TSB results from skin biopsy specimens of patients with mycosis fungoides.
METHODS: We reviewed the records from the Cleveland Clinic Foundation and Northwestern University Medical Center for cases of biopsy-proven mycosis fungoides with results available for skin biopsy TSB from 1987 to 1990.
RESULTS: The detection of clonality by TSB correlates with a higher TNM stage (median stage for positive TSB, IIb vs negative TSB, Ib; P <.05), but not with age at presentation (62 vs 59 years) or duration of disease before presentation (6.2 vs 5.9 years). Although the long-term survival was not significantly different between the 2 groups, there was a trend for patients with positive TSB to die earlier (5-year survival of 67% vs 87%). Disease progression did not correlate with TSB results. Higher clonality rates were noted among patients with biopsy specimens showing a denser lymphoid infiltrate and a higher grade of cytologic atypia.
CONCLUSIONS: Detection of clonality with TSB requires a significant clonal burden. Although clonality can be detected in patients with patches and plaques (T1 and T2) most cases with positive results were obtained from patients with advanced disease (T3 and T4). In our experience, detection of clonality by TSB does not correlate with disease progression and does not carry long-term prognostic implications.New insights into the applicability of T-cell receptor g gene rearrangement analysis in cutaneous T-cell lymphoma
Ning Li and Jag Bhawan
Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA
Journal of Cutaneous Pathology 2001;28 (8), 412-418 Abstract quote
Background: Detection of clonal T-cell receptor (TCR) g gene rearrangement by polymerase chain reaction (PCR) based method is a marker for cutaneous T-cell lymphoma (CTCL) although it can be seen in some benign dermatoses. To determine the accuracy of histologic criteria alone as well as the adjuvant diagnostic role of TCR gene rearrangement for the diagnosis of CTCL, we studied 100 patients with cutaneous T-cell infiltrates by both histology and TCR gene rearrangement.
Methods: The histologic features of the 100 patients were first reviewed by two independent dermatopathologists and their confidence in the diagnosis of CTCL was assigned one of four levels. Then the specimens were analyzed for TCR gene rearrangement either on paraffin-embedded or fresh-frozen tissue by PCR/denaturing gradient gel electrophoresis (DGGE).
Results: The clonality was detected in 100% (15/15) diagnostic of, 84.6% (11/13) consistent with, 57.6% (19/33) suggestive of CTCL. In 9 cases TCR gene rearrangement was compared between formalin-fixed and fresh specimens of the same individual, but with different degrees of histologic confidence (no lower than suggestive). In all cases fresh specimens were positive. In 5 of the cases (2-diagnostic, 2-consistent, 1-suggestive) formalin-fixed specimens were positive as well, and in 4 cases (1-consistent, 3-suggestive) formalin-fixed specimens were negative. When TCR gene rearrangement was studied in eight cases on sequential biopsies from the same patient, the clonality was detected in only one or two biopsies in four cases in which the histologic confidence was low (suggestive or nondiagnostic). The TCR gene rearrangement study showed identical banding patterns in lesions from different clinical stages in most patients. However, we observed that in one case, oligoclonal-banding pattern was seen in initial biopsy with histopathologic consistent with CTCL, while monoclonal banding pattern in more advanced lesion.
Conclusions: Our data have demonstrated that TCR gene rearrangement studies by PCR/DGGE are consistently positive regardless of tissue fixation (formalin-fixed, paraffin-embedded vs. fresh-frozen tissue) and biopsy site when the histologic degree of confidence is very high (diagnostic). So, it may be of less importance as an adjuvant to histopathologic diagnosis for the cases with diagnostic CTCL histology. However, TCR gene rearrangement studies are particularly important in earlier cases with less conclusive histology, which provides strong confirmatory evidence of an evolving CTCL. In these cases, multiple biopsies may be required to establish the diagnosis and analysis of fresh tissue is suggested to increases the sensitivity. Moreover, our observation also suggested that some CTCL might not be monoclonal de novo, but oligoclonal instead.
The value of molecular analysis by PCR in the diagnosis of cutaneous lymphocytic infiltrates.Holm N, Flaig MJ, Yazdi AS, Sander CA.
Department of Dermatology, Ludwig-Maximilians-University Munich, Munich, Germany.
J Cutan Pathol 2002 Sep;29(8):447-52 Abstract quote The diagnosis and classification of cutaneous lymphomas remain a challenge for the clinician and dermatopathologist. This diagnostic dilemma is mainly encountered in the distinction between an early malignant lymphoma and a benign reactive lymphocytic infiltrate (pseudolymphoma).
Until the beginning of the 1980s, our diagnostic tools were limited to the clinical presentation, course, and histopathology in diagnosis and classification of lymphocytic infiltrates. Advances in immunology and, in particular, in molecular genetics with the introduction of the Southern blot technique and the polymerase chain reaction (PCR) have revolutionized the diagnosis of lymphocytic infiltrates by determination of clonality. In some series, more than 90% of cutaneous T-cell lymphomas have a clonal rearrangement of the T-cell receptor gamma-chain gene, as opposed to very low percentages of rearrangement in T-cell pseudolymphomas.
However, the presence of clonality does not necessarily imply malignancy. Cases of pseudolymphomas, lichen planus and pityriasis lichenoides et varioliformis acuta were reported with clonal lymphocytic proliferations. Therefore, care should be exercised in the evaluation of the results of molecular analysis, and these should always be correlated with the clinical, histological and immunophenotypic picture to arrive at the correct diagnosis. It may be expected that the molecular methods for diagnosis of lymphocytic infiltrates will be improved and refined in future, and that sensitivity and specificity will increase.
PERIPHERAL BLOOD CIRCULATING CELLS Peripheral blood involvement in a mycosis fungoides patient with limited skin lesions: phenotypical features and homing molecule pattern.
Quaglino P, Osella-Abate S, Novelli M, Lisa F, Comessatti A, Bernengo MG.
Department of Medical and Surgical Specialties, Section of Dermatology, 1st Dermatologic Clinic, University of Turin, via Cherasco 23, 10126 Turin, Italy.
Eur J Dermatol 2001 Nov-Dec;11(6):560-3 Abstract quote
Peripheral blood involvement in mycosis fungoides (MF) patients is more frequent in the advanced stages and is associated with a worse prognosis.
We report a MF patient with limited patch lesions on her shoulders, upper chest and thighs (T2N0M0) and peripheral blood involvement. Clonality in the peripheral blood was demonstrated by the PCR assay and confirmed by the expansion of the same restricted variable region of the TCR beta-chain (vbeta17) expressed in the cutaneous infiltrate. The patient was treated with fludarabine achieving a complete hematological response followed by an early relapse, whilst the cutaneous lesions remained unchanged. The soluble interleukin-2 receptor levels showed a decrease from baseline levels down to normal values at hematological remission, followed by a further increase.
The low sLex/CLA expression in the cutaneous lymphoid infiltrate could have given rise to a higher recruitment in the peripheral blood.
SERUM IMMUNOGLOBULINS
Increased serum immunoglobulin levels are common in mycosis fungoides and Sezary syndrome.Talpur R, Lifshitz O, Breuer-Mcham J, Duvic M.
Division of Internal Medicine, Department of Dermatology, The University of Texas M. D. Anderson Cancer Center.
J Am Acad Dermatol 2002 Nov;47(5):685-91 Abstract quote BACKGROUND: Patients with cutaneous T-cell lymphoma (CTCL; mycosis fungoides [MF] and Sezary syndrome [SS]) acquire immunodeficiency and opportunistic infections.
OBJECTIVE: We attempted to determine whether abnormalities of humoral immunoglobulin levels are present.
METHODS: A retrospective analysis of serum immunoglobulin levels in patients with CTCL at baseline evaluation at a cancer center was compared to levels in patients with leukemias and levels in healthy control subjects.
RESULTS: A total of 254 of 650 patients with CTCL evaluated between 1987 and 2001 had baseline quantitative immunoglobulin levels. Mean IgG, IgA, and IgM levels were similar among all MF/SS patients versus controls. The percentages of MF/SS patients with elevated levels of each immunoglobulin class were higher than percentages in healthy controls, and elevated IgA levels occurred among late versus early patients (P =.043).
CONCLUSION: High immunoglobulin levels are more frequent in patients with MF and SS than in healthy controls, patients with chronic lymphocytic leukemia, and patients with hairy cell leukemia. High IgA levels are more frequent in late stage MF/SS.
TARC/CCL17 (Chemokine)
Thymus and activation-regulated chemokine (TARC/CCL17) in mycosis fungoides: Serum TARC levels reflect the disease activity of mycosis fungoides.Kakinuma T, Sugaya M, Nakamura K, Kaneko F, Wakugawa M, Matsushima K, Tamaki K.
Department of Dermatology and Department of Molecular Preventive Medicine, University of Tokyo; Department of Dermatology, Fukushima Medical University School of Medicine.
J Am Acad Dermatol 2003 Jan;48(1):23-30 Abstract quote BACKGROUND: Mycosis fungoides (MF) belongs to cutaneous T-cell lymphoma and is clinically divided into 3 stages: patch, plaque, and tumor stage. Thymus and activation-regulated chemokine (TARC/CCL17) is a member of the CC chemokines and is a chemoattractant for CC chemokine receptor 4 (CCR4)- and CC chemokine receptor 8 (CCR8)-expressing cells.
OBJECTIVE: In this study, we examined the involvement of TARC among patients with each stage of MF.
METHODS: We investigated the expression of TARC, CCR4, and CXC chemokine receptor 3 in patients with each stage of MF by immunohistochemistry. We measured serum TARC levels in 20 patients with MF in varying degrees and compared them with 10 patients with psoriasis vulgaris and 10 healthy controls. In addition, we compared serum TARC levels in patients with MF with other laboratory data.
RESULTS: Immunohistochemical staining revealed that TARC was expressed in the lesional keratinocytes in the patch, plaque, and tumor stages. CCR4 was expressed on the epidermotropic cells in both patch and plaque stages and on the large cell-transformed cells in the tumor stage, whereas CXC chemokine receptor 3 was constantly expressed on the small cells in the lesional dermis. Serum TARC levels in patients with MF were significantly higher than those in patients with psoriasis vulgaris or healthy controls. Moreover, serum TARC levels in patients with the tumor stage of MF (n = 5) were remarkably higher than those with patch stage (n = 8) or plaque stage (n = 7). Serum TARC levels significantly correlated with serum lactate dehydrogenase levels (r = 0.62), serum immunoglobulin E levels (r = 0.60), serum soluble interleukin 2 receptor levels (r = 0.72), and serum macrophage-derived chemokine levels (r = 0.70).
CONCLUSION: These data strongly indicate that serum TARC levels are useful for assessing the disease activity of patients with MF and that TARC and CCR4 may be involved in the pathogenesis of MF.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION General Ill defined patches resembling eczema Well demarcated lesions which are red to violaceous, may be pruritic Violaceous to red nodules with occasional ulceration, usually 1 cm or larger VARIANTS Description ACANTHOSIS NIGRICANS-LIKE ACNEIFORM BULLOUS Mycosis fungoides bullosa: Report of a case and review of the literature
Paul H. Bowman, MD
Daniel J. Hogan, MD
I. Daniel Sanusi, MDShreveport, Louisiana
J Am Acad Dermatol 2001;45:934-9 Abstract quote
Mycosis fungoides, the most common type of cutaneous T-cell lymphoma, can manifest in a variety of clinical and histologic forms. Presentation with vesiculobullous lesions is extremely rare.
We report the ninth documented case of mycosis fungoides bullosa in which other concomitant autoimmune blistering diseases were ruled out by negative immunofluorescence. All previously reported cases in the world literature since the first in 1887 are reviewed.
We recommend the following defining criteria for the disease: (1) clinically apparent vesiculobullous lesions, with or without typical mycosis fungoides lesions (patches, plaques, tumors); (2) typical histologic features of mycosis fungoides (atypical lyphoid cells, epidermotropism, Pautrier's microabscesses) with intraepidermal or subepidermal blisters; (3) negative immunofluorescence (both direct and indirect, if possible) to rule out concomitant autoimmune bullous diseases; (4) negative evaluation for other possible causes of vesiculobullous lesions (eg, medications, bacterial or viral infection, porphyria, phototherapy).
CYSTS, EPIDERMAL DYSHIDROTIC Resembling dyshidrotic eczema occurring on hands and feet ERYTHRODERMA Not specific for MF, may be seen in many conditions including drug eruptions, seborrheic dermatitis, and psoriasis. HYPERKERATOTIC AND VERRUCOUS HYPOPIGMENTED
Singh ZN, Tretiakova MS, Shea CR, Petronic-Rosic VM.1Department of Pathology, University of Chicago Hospitals, Chicago, IL, USA.
Hypopigmented mycosis fungoides is an uncommon clinical variant of cutaneous T-cell lymphoma. We hypothesized that hypomelanosis in hypopigmented mycosis fungoides may have a similar mechanism as in vitiligo, a condition in which it is believed that alterations in expression of CD117 (stem cell factor receptor/KIT protein) on epidermal melanocytes and abnormal interactions between melanocytes and surrounding keratinocytes may play a pathogenic role.
To test the hypothesis that similar mechanisms might also explain hypopigmentation in hypopigmented mycosis fungoides, skin specimens from five cases each of hypopigmented mycosis fungoides and vitiligo were studied immunohistochemically for immunophenotype of the infiltrating cells, CD117 (expressed by epidermal melanocytes), and pan melanoma cocktail of antigens (gp100, tyrosinase, and MART-1) expression; cases of conventional mycosis fungoides and normal skin were studied in parallel as controls.
Our findings confirm a predominance of CD8+ neoplastic T cells in hypopigmented mycosis fungoides. Similarly, the epidermal lymphocytic infiltrate in vitiligo was also composed of CD8+ cytotoxic T cells, in contrast to an epidermal infiltrate composed of CD4+ T cells in conventional mycosis fungoides. The average number of epidermal CD117 expressing cells followed the same pattern of decreased expression in hypopigmented mycosis fungoides as in vitiligo, whereas the levels in conventional mycosis fungoides were higher, and similar to that observed in normal skin. Furthermore, a decreased number of melanocytes per high-power field of the length of the biopsy was present in hypopigmented mycosis fungoides and vitiligo, as compared with either conventional mycosis fungoides or normal skin, suggesting a correlation between decreased expression of CD117 and decreased number of melanocytes.
We propose that decreased expression of CD117 and its downstream events in melanocytes may be initiated by cytotoxic effects of melanosomal-antigen-specific CD8+ neoplastic T lymphocytes, resulting in destabilization of CD117 and leading to dysfunction and/or loss of melanocytes in the epidermis of hypopigmented mycosis fungoides.
- "Hypopigmented mycosis fungoides" is not always mycosis fungoides!
Werner B, Brown S, Ackerman AB.
University of Parana, Curitiba, PR, Brazil.
Am J Dermatopathol. 2005 Feb;27(1):56-67. Abstract quote
We conducted a critical review of hypopigmented mycosis fungoides in historical perspective with emphasis on criteria clinical and histopathologic for diagnosis of that lymphoma as they are set forth in every article ever written about it. Toward that end, we undertook analysis of each article in the medical literature that mentioned hypopigmentation in mycosis fungoides (34 in toto). Each was scrutinized regarding content, photographs of lesions clinical pictured, and photomicrographs.
On the basis of all the information in the 34 publications available to us, we made a determination about which patients had mycosis fungoides without doubt, which surely did not, and which about whom no judgment could be made by us because too little data requisite for such a decision was provided, especially in terms of photographs of lesions clinical and of photomicrographs. To date, 106 patients with "hypopigmented mycosis fungoides" have been reported on. Features clinical and findings histopathologic in 23 of those 106 patients were sufficient to permit us to determine, with a high degree of confidence, whether or not a particular patient truly had mycosis fungoides.
In our judgment, 19 patients did have mycosis fungoides, whereas at least four patients did not. In regard to the other 83 patients, the information provided by the authors simply was not sufficient to allow us to come to a decision that we could justify.
Hypopigmented mycosis fungoides in Caucasian patients: a clinicopathologic study of 7 cases.Ardigo M, Borroni G, Muscardin L, Kerl H, Cerroni L.
Department of Dermatology, University of Graz, University of Pavia, Rome.
J Am Acad Dermatol. 2003 Aug;49(2):264-70. Abstract quote BACKGROUND: Hypopigmented mycosis fungoides (MF) is a rare variant of cutaneous T-cell lymphoma. It is more frequent in dark-skinned or Asian patients, particularly children. Only 9 cases in Caucasian patients have been reported in the literature so far.
OBSERVATION: We describe 7 Caucasian patients (2 children and 5 adults) with hypopigmented MF. Histologic examination confirmed the diagnosis in all cases. The phenotype of neoplastic lymphocytes was T helper in 4 cases and T suppressor in 3 (2 of them children). Monoclonality of the T lymphocytes could be detected in hypopigmented lesions in all 7 cases with the use of a polymerase chain reaction technique. In 4 patients, polymerase chain reaction analysis of T-cell receptor-gene rearrangement after laser-based microdissection of the specimen revealed that the monoclonal population of T lymphocytes was confined mainly to the epidermis.
CONCLUSION: Hypopigmented lesions of MF can be observed in Caucasian patients. Children affected by MF often present with this rare clinical variant of the disease. Persistent or unusual hypopigmented lesions should be subjected to biopsy to avoid delay in the diagnosis of MF, especially in children.Hypopigmented mycosis fungoides: case reports and literature review.
Qari MS, Li N, Demierre MF.
The Skin Oncology Program, Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA.
J Cutan Med Surg 2000 Jul;4(3):142-8 Abstract quote
BACKGROUND: Hypopigmented mycosis fungoides is a rare variant of mycosis fungoides (MF) that usually has a predilection for young individuals with dark complexion.
OBJECTIVE: The aim is to describe new cases of hypopigmented MF with confirmed T-cell receptor gene rearrangement analysis.
METHODS: This article includes case reports and a literature review.
RESULTS: Three out of four hypopigmented MF patients had a positive TCR gene rearrangement. A fifth patient is reported who had hypopigmented mycosis fungoides and classical Pautrier microabscesses, for whom no TCR gene rearrangement analysis was performed.
CONCLUSION: Although hypopigmented MF has a predilection for dark-complexioned populations, it can also affect Caucasian patients. In challenging cases, polymerase chain reaction can be a useful method for detecting early cases of hypopigmented MF.
Hypopigmented Mycosis Fungoides: Frequent Expression of a CD8+ T-Cell Phenotype.Shabrawi-Caelen LE, Cerroni L, Medeiros LJ, McCalmont TH.
Department of Dermatology (L.E.S.-C., L.C.), University of Graz, Gras, Austria; the Division of Pathology and Laboratory Medicine (L.J.M.), University of Texas-M.D. Anderson Cancer Center, Houston, Texas; and the Departments of Pathology and Dermatology (T.H.M.), University of California, San Francisco, California, U.S.A.
Am J Surg Pathol 2002 Apr;26(4):450-457 Abstract quote Hypopigmented mycosis fungoides (MF) is a form of cutaneous T-cell lymphoma in which hypopigmentation occurs in the absence of classic lesions of MF. Hypopigmented MF predominantly affects people with dark complexions. The natural history of this variant of cutaneous T-cell lymphoma is similar to that of conventional MF, although the disease onset is usually in childhood or adolescence. In a retrospective study we evaluated the clinical, histopathologic, immunohistochemical, and molecular characteristics of hypopigmented MF in 15 patients. Similar to other reports, the disease onset occurred in childhood and adolescence in most of the cases. The survival rate was comparable with that of classic MF. We did not observe progression to systemic disease or lymph node involvement.
Histopathologically hypopigmented lesions were indistinguishable from hyperpigmented or erythematous patches. On immunohistochemical analysis a predominantly CD8+ infiltrate was detected in the majority of cases (nine of 15 patients). To determine whether epidermotropic CD8+ T cells represent the malignant T-cell clone or whether these cells are innocent, tumor-infiltrating T lymphocytes, we performed microdissection of epidermotropic CD8+ T cells and analyzed T-cell receptor-gamma chain gene for rearrangements. The epidermotropic CD8+ T lymphocytes showed clonal T-cell receptor gene rearrangement and therefore represented the malignant T-cell clone.
We conclude that hypopigmented MF tends to occur in young people and that it belongs to the group of CD8+ cutaneous T-cell lymphomas in the majority of cases.
ICHTHYOSIFORM
Ichthyosiform mycosis fungoides: An atypical variant of cutaneous T-cell lymphoma.
Hodak E, Amitay I, Feinmesser M, Aviram A, David M.
J Am Acad Dermatol. 2004 Mar;50(3):368-74. Abstract quote
BACKGROUND: Acquired ichthyosis is a known paraneoplastic sign of lymphoproliferative malignancies, with histopathologic findings that are nonspecific, revealing no insinuation of the underlying neoplasm. Ichthyosiform eruption as a specific manifestation of mycosis fungoides (MF), ie, ichthyosiform MF, is, however, regarded as rare and to date has been reported in only a few cases.
OBJECTIVE: We sought to study the clinical, histopathologic, immunohistochemical, and genotypic features of patients with ichthyosiform MF.
METHODS: The files of patients with MF seen during the past 8 years in our department were reviewed to search for cases of ichthyosis-like MF.
RESULTS: Seven patients, comprising 3.5% of the patients seen with MF, had an ichthyosiform eruption with histopathologic features characteristic of early MF. In 2 patients it was the sole manifestation of the disease and in 5 patients it appeared either in conjunction with conventional patches and/or plaques or with follicular lesions. Immunohistochemically, all showed a predominance of CD3(+) CD4(+), except for 1 patient in whom the epidermotropic T cells were predominantly CD8(+). In 3 of the 7 patients clonality could be demonstrated by polymerase chain reaction. None had extracutaneous involvement. All had an indolent course of the disease and responded well to skin-targeted therapies.
CONCLUSIONS: Ichthyosiform MF is yet another atypical clinical variant of cutaneous T-cell lymphoma that is not as rare as reflected in the literature. It may be the sole manifestation of the disease but also may appear in conjunction with conventional or follicular MF lesions.INVISIBLE Invisible mycosis fungoides: A diagnostic challenge
Ramon M. Pujol, MD, etal.
J Am Acad Dermatol 2000;42:324-8 Abstract quote
We describe a 76-year-old woman who presented persistent generalized pruritus as the only cutaneous manifestation of a cutaneous T-cell lymphoma (mycosis fungoides). No cutaneous lesions were observed throughout the patient's course. Skin biopsies obtained from normal-looking pruritic skin revealed a discrete perivascular lymphocytic infiltrate in the upper dermis and focal intraepidermal clusters of atypical lymphoid cells (Pautrier’s microabscesses). PCR analysis of TCR-gamma gene disclosed a monoclonal T-cell rearrangement. Sequencing of the PCR monoclonal product identified the J8V2C2 TCR gene rearrangement.
This observation illustrates the existence of a peculiar and exceedingly rare form of mycosis fungoides characterized only by persistent pruritus unresponsive to several therapeutic approaches. The diagnostic difficulties of this rare variant are stressed.
Invisible mycosis fungoides: A diagnostic challenge.Pujol RM, Gallardo F, Llistosella E, Blanco A, Bernado L, Bordes R, Nomdedeu JF, Servitje O.
Departments of Dermatology, Pathology, and Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona; Hospital Princeps d'Espanya, Barcelona; Hospital Josep Trueta, Girona; and Institut de Recerca Oncologica, Barcelona.
J Am Acad Dermatol 2002 Aug;47(2 Pt 2):S168-71 Abstract quote We describe a 76-year-old woman who had persistent generalized pruritus as the only cutaneous manifestation of a cutaneous T-cell lymphoma (mycosis fungoides). No cutaneous lesions were observed throughout the patient's course.
Skin biopsy specimens obtained from normal-looking pruritic skin revealed a discrete perivascular lymphocytic infiltrate in the upper dermis and focal intraepidermal clusters of atypical lymphoid cells (Pautrier's microabscesses). PCR analysis of TCR-gamma gene disclosed a monoclonal T-cell rearrangement. Sequencing of the PCR monoclonal product identified the J(8)V(2)C(2) TCR gene rearrangement.
This observation illustrates the existence of a peculiar and exceedingly rare form of mycosis fungoides characterized only by persistent pruritus unresponsive to several therapeutic approaches. The diagnostic difficulties of this rare variant are stressed.
ORAL
From the *Departments of Pathology and Laboratory Medicine; and daggerDepartment of Dermatology, Indiana University, Indianapolis, IN.
We report a case of a 75-year-old man with a cutaneous CD4+CD56+ hematodermic neoplasm. CD4+CD56+ hematodermic neoplasms are rare and commonly present as cutaneous lesions.
This is an important diagnosis in the differential diagnosis of cutaneous hematologic malignancies because of the extremely poor prognosis.PALMARIS ET PLANTARIS
J Am Acad Dermatol. 2006 Mar;54(3):466-71. Abstract quote
BACKGROUND: Mycosis fungoides palmaris et plantaris (MFPP), characterized by hyperkeratotic patches or plaques confined to the palms and soles, is rare and easy to misdiagnose because of the clinical similarity to psoriasis, cutaneous inflammatory dermatoses, and dermatophytic infections. The literature about MFPP mostly consists of case reports with short-term follow-up.
OBJECTIVE: Our purpose was to evaluate the clinicopathologic features, T-cell receptor (TCR) gene rearrangement findings, and prognosis of MFPP.
PATIENTS AND METHODS: This retrospective study has been reviewed in the clinicopathologic, TCR gamma gene rearrangement findings and follow-up study of 12 patients with MFPP.
RESULTS: The duration of diseases ranged from 9 months to 25 years with a mean duration of 5.3 years. Clinically, hyperkeratotic patches and plaques were observed in all cases, with 6 cases having developed on the palms and soles and 6 cases on the palms only. In TNM classifications, all cases were confined to T1N0M0 (stage IA) showing an early stage of mycosis fungoides (MF). Histopathologic findings revealed marked hyperkeratosis, parakeratosis with plasma, epidermotropism, convoluted lymphocytes, haloed lymphocytes, dense infiltrate of lymphocytes in all 12 cases (100%), Pautrier's microabscess in 9 cases (75%), a wiry bundle of collagen in 11 cases (91.7%) and basilar epidermotropism in 3 cases (25%). TCR gamma gene rearrangement was performed except for one case and monoclonality was detected in 10 of 11 cases. In the comparison group with cutaneous inflammatory dermatoses, all cases showed polyclonality. Treatment was done with Re-PUVA (acitretin and PUVA), ultraviolet A1, as well as systemic acitretin and methotrexate. Most patients showed a good response. In the follow-up study of 9 cases for a mean period of 47.6 months, only one patient's skin lesions were extended to the trunk and face, but the other patients had no sign of extracutaneous involvement.
LIMITATIONS: These results were obtained from patients with MFPP in Korea. A cooperative study with other ethnic groups will be helpful.
CONCLUSIONS: If a patient has recalcitrant palmoplantar dermatosis, MFPP should be suspected and histopathologic studies with TCR gene rearrangement should be done for early diagnosis of MFPP.
PAPULAR
- Papular mycosis fungoides: a new clinical variant of early mycosis fungoides.
Kodama K, Fink-Puches R, Massone C, Kerl H, Cerroni L.
Department of Dermatology, Medical University of Graz, Graz, Austria.
J Am Acad Dermatol. 2005 Apr;52(4):694-8. Abstract quote
BACKGROUND: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. In early stages of the disease many different clinicopathologic variants have been observed.
OBSERVATION: We report 6 patients with early manifestations of MF characterized by the sole presence of papules which, unlike the papules of lymphomatoid papulosis, did not show a tendency for spontaneous resolution. Histologic examination confirmed the diagnosis of MF in all cases. Immunohistochemical staining for CD30 was negative in all cases. Follow-up data showed the nonaggressive behavior of the disease, confirming that the lesions were not manifestations of advanced MF.
CONCLUSION: Papular MF is a new variant of early MF characterized by the presence of papules in the absence of more conventional early lesions (patches) of the disease. This variant should be added to the long list of clinicopathologic subtypes of MF.PERIORAL DERMATITIS-LIKE PUSTULES TUMOR D'EMBLEE Tumors develop without an antecedent patch or plaque stage. UNILESIONAL Unilesional mycosis fungoides: a study of seven cases.
Hodak E, Phenig E, Amichai B, Feinmesser M, Kuten A, Maron L, Sahar D, Bergman R, David M.
Department of Dermatology, Institute of Oncology, Petah Tiqva, Israel.
Dermatology 2000;201(4):300-6 Abstract quote
BACKGROUND: Unilesional mycosis fungoides (MF) is a rare variant of cutaneous T-cell lymphoma (CTCL), characterized by a solitary lesion clinically and by histopathological features indistinguishable from those of MF, and typically having a benign course.
OBJECTIVE: To describe the clinicopathological features of a series of patients with unilesional MF.
METHODS: The records of cases of unilesional MF identified during a 10-year period in two medical departments were reviewed.
RESULTS: There were 7 patients: 6 males, 1 female; mean age at the time of diagnosis: 32 years; age range: 12-58 years; 3 were below the age of 18 years. The mean pretherapy follow-up period was 9