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
Pathogenesis Apoptosis and CD95 (Fas)
Apoptosis and Galectin-1
T-cell Chemokine Receptor
Other Diagnostic Testing
TARC/CCL17 (Chemokine) Gross Appearance and Clinical Variants Acanthosis-nigricans
Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis and Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS CTCL
Cutaneous T-cell lymphoma
Cerebriform T-cell lymphoma
Incidence of Cutaneous T-Cell Lymphoma in the United States, 1973-2002
Vincent D. Criscione, AB; Martin A. Weinstock, MD, PhD
Dermatoepidemiology Unit, VA Medical Center, Department of Dermatology, Rhode Island Hospital, and Departments of Dermatology and Community Health, Brown University, Providence, Rhode Island.
Arch Dermatol. 2007;143:854-859. Abstract quote
Objective To describe incidence trends for cutaneous T-cell lymphoma (CTCL) in the United States.
Design Population-based study.
Setting Data were obtained from 13 population-based cancer registries of the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute from 1973 through 2002.
Participants A total of 4783 cases of CTCL were identified for the period 1973 through 2002.
Main Outcome Measure Diagnosis of CTCL.
Results The overall annual age-adjusted incidence of CTCL was 6.4 per million persons. Annual incidence increased by 2.9 x 10–6 per decade over the study period. Incidence was higher among blacks (9.0 x 10–6) than among whites (6.1 x 10–6) and was higher among men (8.7 x 10–6) than among women (4.6 x 10–6). The racial differences in incidence decreased with age, while the sex differences increased with age and decreased over time. Substantial geographic variation in incidence was found. Incidence was correlated with high physician density, high family income, high percentage of population with a bachelor's degree or higher, and high home values. Changes in International Classification of Diseases for Oncology (ICD-O) morphologic definitions have resulted in the redistribution of the cases of CTCL among specific subclassifications.
Conclusions The continued rise in incidence of CTCL is substantial, and the cause of this increase is unknown. The racial, ethnic, sex, and geographic differences in incidence may be of etiologic importance. Changes in ICD-O definitions have made it difficult to evaluate incidence trends for subclassifications of CTCL such as mycosis fungoides. In addition, these changes resulted in the creation of ambiguous histologic codes, which may have caused coding errors. These errors along with the lack of independent verification are limitations of our study. An epidemiological investigation using population-based data is important to better understand this disorder.
- Familial mycosis fungoides: report of 6 kindreds and a study of the HLA system.
Hodak E, Klein T, Gabay B, Ben-Amitai D, Bergman R, Gdalevich M, Feinmesser M, Maron L, David M.
Department of Dermatology, Sackler Faculty of Medicine, Tel-Aviv University, Petah Tiqva, Israel.
J Am Acad Dermatol. 2005 Mar;52(3 Pt 1):393-402. Abstract quote
BACKGROUND: The familial occurrence of mycosis fungoides (MF) has been reported only in 8 families. Recently, the HLA class II alleles DRB1* 11 and DQB1* 03 have been found to be significantly increased for patients with sporadic MF, suggesting a possible immunogenetic basis for the pathogenesis of this malignancy.
OBJECTIVE: We sought to detect familial occurrences of MF, to describe familial features, and to investigate the possible association or linkage with the HLA system in such cases.
METHODS: The files of 300 patients with MF were reviewed to search for familial occurrence in at least two first-degree relatives. A group of 252 healthy unrelated individuals served as control subjects. Tissue typing for HLA class I was performed using the microlymphocytotoxicity technique. DNA-based analysis for DRB1* and DQB1* alleles was performed using polymerase chain reaction amplification.
RESULTS: Six families comprising 12 Jewish patients (9 male and 3 female) were detected: in 5, two first-degree relatives had MF; and in one, one member had MF and another had parapsoriasis en plaque. There were 5 families with two affected siblings and one family with a parent-child pair. In all but one family, the age of onset, clinical features, and response to therapy were similar to those in sporadic MF. One family, however, was exceptional: both affected siblings were children and both exhibited a similar but unusual morphology in the form of a hypopigmented variant of MF in conjunction with a psoriasiform variant. The allele frequency of HLA DQB1* 03 was found to be significantly greater among the patients than in the control group (66.7% vs 33%, respectively; P = .027), supporting an association of this allele with familial MF. Analysis of the HLA typing in the affected sibling pairs, when grouped together, did not support linkage to the HLA locus because no segregation distortion could be demonstrated ( P = .76).
CONCLUSIONS: Familial aggregation of MF among Israeli Jews may not be as rare as is reflected in the literature. This familial clustering, together with the detection of certain HLA class II alleles with this malignancy (sporadic and familial), suggests that genetic factors may play a role in MF.
- Poor prognosis in non-Caucasian patients with early-onset mycosis fungoides.
Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.
- J Am Acad Dermatol. 2009 Feb;60(2):231-5. Abstract quote
BACKGROUND: Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is most often seen in middle-aged to elderly men.
OBJECTIVE: We conducted a retrospective study of the demographics and prognosis of patients with onset of MF before age 40 years.
METHODS: Demographic data (age, sex, and race) and histology from 1074 patents with cutaneous T-cell lymphoma were stratified by age of onset and race and analyzed using Chi-square test.
RESULTS: Women presented before age 40 years more often than men (P = .038). Early onset of MF was diagnosed in 30 of 92 (32.6%) African American (AA), 31 of 87 (35.6%) Hispanic, and 103 of 809 (12.7%) Caucasian patients. MF was significantly more common in AA (P = .0008) and Hispanic (P = .0002) patients. Early-onset MF was more common among 21 of 60 AA women (35%, P = .0174) and 19 of 40 Hispanic women (47.5%, P = .0002) than among 50 of 350 Caucasian women (14.5%). Progression from initial TNM stage occurred in only 5 (10%) Caucasian, one (5%) Hispanic, and 8 (38%) AA women who presented before age 40 years. Six of 8 AA women who progressed died of their disease whereas two were long-term survivors after allogeneic transplantation.
LIMITATIONS: This was a retrospective study at one cancer center.
CONCLUSION: Although MF is considered to be a disease of middle-aged men, early-onset MF is more common among AA and Hispanic women. AA women with early onset may have a poor prognosis and should be considered for more aggressive therapy, including allogeneic transplantation.
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 NHL
Among 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
Epstein-Barr Virus–Negative Hodgkin’s Lymphoma After Mycosis Fungoides: Molecular Evidence for Distinct Clonal Origin
Mod Pathol 2001;14:91-97 (Quoted from abstract)
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.
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.
- Arch Dermatol. 2007 Jan;143(1):45-50. Abstract quote
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.
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 accumulation
In 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-selectin
APOPTOSIS 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.
Expression of apoptosis markers on peripheral blood lymphocytes from CTCL patients during extracorporeal photochemotherapy
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.
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.
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-12
LOSS OF HETEROZYGOSITY
- Loss of Heterozygosity Analysis Identifies Genetic Abnormalities in Mycosis Fungoides and Specific Loci Associated With Disease Progression.
*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.
- Am J Surg Pathol. 2007 Oct;31(10):1552-1556. Abstract quote
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 Constitutive expression of NK-kappaB
Hum Pathol 2000:31:1482-1490
Immunoperoxidase study of 23 cutaneous lesions and single lymph node biopsy
Neoplastic 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 inhibition
T-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.
CHARACTERIZATION FLOW CYTOMETRY
- Usefulness of flow cytometry in the diagnosis of mycosis fungoides.
Department of Dermatology, Ireland Cancer Center of University Hospitals of Cleveland/Case Western Reserve University, Cleveland, Ohio 44106, USA.
- J Am Acad Dermatol. 2007 Sep;57(3):454-62. Abstract quote
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.
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.
- T-cell clonality analysis in biopsy specimens from two different skin sites shows high specificity in the diagnosis of patients with suggested mycosis fungoides.
Department of Pathology, Stanford University, Stanford, California 94035, USA.
- J Am Acad Dermatol. 2007 Nov;57(5):782-90. Abstract quote
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 -chain gene rearrangement in lymph node DNA by PCR also were more likely to have a poor outcome (HR, 5.1; P<.001), but it was a less powerful predictor than skin stage. Even when the skin stage, presence or absence of lymphadenopathy, and histologic lymph node score were known for the patient, Southern blot analysis still added to prediction of a poor outcome (HR, 9.3; P = .007), whereas PCR provided no statistically significant additional information on outcome.
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.
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.
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.
CHARACTERIZATION General Patch Ill defined patches resembling eczema Plaque Well demarcated lesions which are red to violaceous, may be pruritic Tumor 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, MD
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
- Mod Pathol. 2006 Sep;19(9):1255-60. Abstract quote
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 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 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.
- Am J Dermatopathol. 2007 Feb;29(1):59-61. Abstract quote
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 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 years (range: 2-20 years). In 5 patients, the eruption consisted of a characteristic patch or plaque of MF located on the trunk or upper extremity; in 2 it was atypical - in 1, a hypopigmented patch, and in 1, a plaque indistinguishable from MF-associated follicular mucinosis. Histopathologically all the lesions exhibited features characteristic of MF, with CD3+ lymphoid cells. In 6 cases (with available fresh frozen tissue) there was a predominance of CD3+ CD4+ cells; in 1 of 5 there was deletion of CD7, and in 3 of 5 there was an overexpression of IL-2 receptor. T-cell receptor gamma gene rearrangement was found in 1 of 4 cutaneous lesions tested; in 2 cases it was found in the blood but not in the skin. Treatment modalities included localized electron beam, excision, topical nitrogen mustard or topical steroids and sunbathing, resulting in all cases in a sustained complete clinical response. In 1 patient, however, there were 2 local recurrences and in yet another patient there was distant cutaneous spread 3.5 years after therapy.
CONCLUSIONS: Unilesional MF is a rare variant of CTCL, has heterogeneous clinical manifestations and can affect any age group, including children. The histopathological and immunophenotypical features are in general indistinguishable from those observed in multilesional MF. Although it is a unifocal event, there may occasionally be cutaneous spread with the appearance of noncontiguous lesions, even a long time after therapy. Whether all cases represent minimal-stage IA MF or whether some are actually T-cell pseudolymphoma remains to be clarified.
EXTRACUTANEOUS SITES BONE MARROW Bone Marrow Histopathologic and Molecular Staging in Epidermotropic T-Cell Lymphomas
Vincent Sibaud, MD
Marie Beylot-Barry, MD, PhD
Rodolphe Thiébaut, MD, etal.
Am J Clin Pathol 2003;119:414-423 Abstract quote
This study was undertaken to determine the prognostic value of bone marrow histopathologic and molecular analyses in 53 patients with mycosis fungoides and 7 with Sézary syndrome.
Bone marrow was involved in only 1 patient with Sézary syndrome, clinical stage IVA, before bone marrow biopsy. An ambiguous T-cell infiltrate was observed in 8 patients but was not associated with disease progression. The bone marrow specimen was normal in 51 patients. Monoclonality was detected in the skin specimen in 44 cases; an identical T-cell clone in the blood specimen was found in 21 of them and, in 16 of the 21 patients, in bone marrow specimens without histologic correlation. Multivariate analysis confirmed that clinical stage and detection by polymerase chain reaction of an identical T-cell clone in skin and blood specimens had an independent prognostic value. No further prognostic value was observed for the presence of a T-cell clone in bone marrow specimens.
Our data do not support the need for bone marrow examination in patients with mycosis fungoides/Sézary syndrome.
Marrow involvement in cutaneous T-cell lymphoma. A clinicopathologic study of 60 cases.
Salhany KE, Greer JP, Cousar JB, Collins RD.
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Am J Clin Pathol 1989 Dec;92(6):747-54 Abstract quote
Cutaneous T-cell lymphomas (CTCLs), including Sezary syndrome, are generally assumed to spare the marrow until the disease is far advanced.
The authors reviewed marrow sections from 60 patients with CTCL, looking carefully for aggregates of cerebriform cells, and found marrow involvement in 13 patients (21.7%); another 19 had abnormal lymphoid nodules that were not diagnostic of involvement, and 28 had marrows with negative results.
Involved marrows had nodules or infiltrates of dysplastic cerebriform cells that were often subtle, without a significant increase in cellularity; only one case showed massive involvement. Patients with CTCL with an infiltrative component of marrow involvement had associated peripheral blood involvement (eight of eight), generalized erythroderma (six of eight), lymph node involvement (five of eight), visceral progression (five of eight), and significantly shortened median survival compared with patients with CTCL with negative marrows (11 months and 70 months, respectively; P = 0.007).
In contrast, five patients with nodules of tumor in the marrow but lacking an infiltrative component did not have peripheral blood involvement; only one patient had adenopathy or visceral progression develop, and two patients have died. Significant hematologic abnormalities were generally absent. Eight of 13 patients with marrow involvement had advanced skin disease, but skin disease was limited to plaques in five patients. Eight patients had marrow involvement develop within three months of initial diagnosis.
Thus, marrow involvement occurs in approximately 20% of patients with CTCL, is often present at initial diagnosis, and is associated with widespread dissemination and shortened survival time when an infiltrative component is present.
CENTRAL NERVOUS SYSTEM
Brainstem involvement by mycosis fungoides in a patient with large-cell transformation: a case report and review of literature.
Li N, Kim JH, Glusac EJ.
Department of Pathology, and Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
J Cutan Pathol. 2003 May;30(5):326-31 Abstract quote
BACKGROUND: Central nervous system (CNS) involvement by mycosis fungoides (MF) is rare. As compared to meningeal involvement, intraparenchymal spread is especially rare. It is usually seen in advanced disease in conjunction with lymph node or visceral involvement. However, CNS involvement in the absence of progressive skin lesions or other extracutaneous involvement has been reported rarely in patients with transformed MF.
METHOD: Case report and review of literature.
RESULTS: A 71-year-old female with long-standing MF developed lymphomatous CNS involvement 10 years after the diagnosis of tumor stage MF. At this time, the patient presented with a transient episode of garbled speech followed by generalized weakness. Computerized tomography scan (CT scan) and magnetic resonance imaging scan (MRI scan) of the head revealed a subcortical lesion in the left temporo-frontal lobe. Cerebrospinal fluid (CSF) examination showed atypical T cells, and brain biopsy confirmed parenchymal involvement by T-cell lymphoma. Meanwhile, a biopsy of a skin lesion showed large-cell transformation. No lymph node or other systemic involvement was noted at this time, and the patient was treated with chemotherapy. Twelve months later, the patient developed recurrent CNS lymphoma with multiple organ involvement and expired soon thereafter.
CONCLUSIONS: This case illustrates the importance of awareness of the possibility of CNS involvement by MF, especially in transformed MF. CNS involvement may be the only site of extracutaneous involvement in patients with transformed MF, and mental status changes warrant CNS surveillance for this disease.
Esophageal involvement by cutaneous T-cell lymphoma, mycosis fungoides type: diagnosis by endoscopic biopsy.
Kim OD, Cantave I, Schlesinger PK.
Department of Medicine, Veterans Administration, West Side Medical Center, Chicago, IL 60612.
J Clin Gastroenterol 1990 Apr;12(2):178-82 Abstract quote
A patient with long-standing cutaneous T-cell lymphoma, mycosis fungoides type (CTCL-MF), developed dysphagia, odynophagia, and weight loss. Endoscopic biopsy of esophageal mucosa demonstrated involvement by CTCL-MF.
Although extracutaneous spread of CTCL-MF is common, esophageal involvement is unusual and to our knowledge has not previously been diagnosed antemortem.
Histologic assessment of lymph nodes in mycosis fungoides/Sezary syndrome (cutaneous T-cell lymphoma): clinical correlations and prognostic import of a new classification system.
Sausville EA, Worsham GF, Matthews MJ, Makuch RW, Fischmann AB, Schechter GP, Gazdar AF, Bunn PA Jr.
Hum Pathol 1985 Nov;16(11):1098-109 Abstract quote
Mycosis fungoides and the Sezary syndrome share common cutaneous histopathologic features, and this spectrum of malignant disease is referred to here as cutaneous T-cell lymphoma (CTCL).
A method (LN classification) for describing the histopathologic features of lymph nodes in CTCL is presented.
In this system, lymph node biopsy specimens are scored according to the number of atypical lymphoid cells in T-cell-dependent paracortical zones and the preservation or distortion of the lymph node architecture. Lymph node architecture is preserved in lymph nodes scored LN1 to LN3, and these nodes may have coexistent dermatopathic change. LN1 nodes have single infrequent atypical lymphocytes in paracortical T-cell regions. LN2 nodes have small clusters of paracortical atypical cells. LN3 nodes have large clusters of atypical cells. LN4 nodes are partially or totally effaced by atypical cells. This system was used to classify 96 lymph node biopsy specimens obtained within six months of the initial diagnosis of CTCL; no LN1 nodes, 37 LN2, 44 LN3, and 15 LN4 nodes were found. The LN class was significantly correlated with the extent of skin, blood, and visceral involvement, as well as with survival. Patients with LN2 lymph nodes have an estimated five-year survival of 70 per cent, while patients with LN3 and LN4 nodes have estimated five-year survivals of 30 and 15 per cent, respectively. The survival differences between the LN subgroups were all significant (P less than 0.05).
The LN classification system was clearly shown to be reproducible among experienced pathologists. The LN system for the histopathologic classification of lymph nodes in CTCL is of prognostic value and should be used to assess lymph node biopsies in patients with CTCL.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL The histologic criteria is not uniformly agreed upon. The following articles highlight some of the salient histological parameters that have been used to establish the diagnosis
- Histopathologic Features of Early (Patch) Lesions of Mycosis Fungoides: A Morphologic Study on 745 Biopsy Specimens From 427 Patients.
Massone C, Kodama K, Kerl H, Cerroni L.
From the *Department of Dermatology, Medical University of Graz, Graz, Austria; daggerDiSEM, Section of Dermatology, University of Genoa, Genoa, Italy; and double daggerDepartment of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Am J Surg Pathol. 2005 Apr;29(4):550-560. Abstract quote
The histologic diagnosis of early mycosis fungoides (MF) is one of the most vexing problems in dermatopathology. We reviewed the histopathologic features of 745 biopsy specimens from 427 patients (male:female = 277:150; median age, 52 years; range, 3-95 years) with early (patch) lesions of MF collected from the lymphoma database of the Department of Dermatology of the Medical University of Graz (Austria).
In all patients, the diagnosis was established by clinicopathologic correlation. The most common histopathologic pattern consisted of a band-like or patchy lichenoid infiltrate admixed with coarse bundles of collagen in the superficial dermis. Epidermotropism of lymphocytes was observed in most cases in one or more forms (single lymphocyte epidermotropism, 22%; basilar lymphocytes, 23%; Pautrier's microabscesses, 19%; "haloed" lymphocytes, 40%; disproportionate exocytosis, 17%; pagetoid epidermotropism, 3%). In 4% of cases, epidermotropism was completely missing. Atypical lymphocytes were present only in 9% of cases. Features of interface dermatitis were observed in 59% of cases. Other unusual findings were the presence of necrotic keratinocytes (23%), melanophages (8%), and extravasated erythrocytes (4%). In 28 patients, two or more biopsies taken on the same day at different body sites showed different histopathologic aspects, underlying the protean features of MF even in a single patient at a given time.
Our study expands previous observations on histopathologic features of early lesions of MF. Although sometimes the histopathologic features are not diagnostic, they should be considered consistent with MF and do not rule out the diagnosis.
Interrater and intrarater reliability of histologic criteria in early cutaneous T-cell lymphoma.
Santucci M, Burg G, Feller AC.
Dermatol Clin 1994; 12: 323.
Evaluation of 73 MF biopsies, each reviewed on two separate occasions by three expert histopathologists
An accurate diagnosis of MF was rendered on both readings approximately half of the time
Control cases were accurately identified on both occasions approximately 40% of the time
Cutaneous T-cell lymphoma. Evaluation of pretreatment skin biopsy specimens by a panel of pathologists.
Olerud JE, Kulin PA, Chew DE, et al.
Arch Dermatol 1992; 128: 501.
This study labeled 52% of control cases “suspicious for” MF and 6% of control cases diagnostic of MF
This suggests that lowering the threshold for a diagnosis of MF leads to significant overcalls
Interrater and intrarater variabilities in the evaluation of cutaneous lymphoproliferative T-cell infiltrates.
Burg G, Zwingers T, Staegemeir E, Santucci M.
Dermatol Clin 1994; 12: 311.
The histologic spectrum of mycosis fungoides/Sezary syndrome (cutaneous T-cell lymphoma). A review of 222 biopsies, including newly described patterns and the earliest pathologic changes.
Shapiro PE, Pinto FJ.
Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520.
Am J Surg Pathol 1994 Jul;18(7):645-67Abstract quote
We studied 222 skin biopsies of mycosis fungoides and Sezary syndrome (cutaneous T-cell lymphoma [CTCL]) to document the huge histologic spectrum and to evaluate the earliest histologic changes.
Our results indicate that CTCL produces practically all of the patterns used for diagnosing inflammatory skin disease: superficial or superficial and deep perivascular without epidermal changes; spongiotic; psoriasiform, with or without a lichenoid infiltrate; interface, including lichenoid without vacuolar alteration, lichenoid with vacuolar alteration, and vacuolar alteration without a lichenoid infiltrate; follicular, with or without mucin; nodular and diffuse; vasculitis; vesicular; and panniculitis.
Unusual examples resembling granuloma annulare, gyrate erythema, lichen planus, and pityriasis lichenoides were seen.
To further document the spectrum within each pattern, we analyzed many variables, such as lymphocytic atypia, epidermotropism, epidermal contour, and composition of the dermal infiltrate.
Common clues to the diagnosis of CTCL include epitheliotropism with little spongiosis; lymphocytes lined up along the basal layer; hyperconvoluted lymphocytes; and broad areas of slight hyperorthokeratosis that is compact or laminated, with subtle interspersed parakeratosis.
Less common clues include Pautrier's microabscesses; granulomatous foci; coexistence of plasma cells and eosinophils; and rounded, hyperplastic rete ridges adjacent to flattened rete.
The earliest changes of CTCL appear to be a sparse, superficial perivascular infiltrate with slight or no epidermal hyperplasia and with rare lymphocytes in the lower epidermis, especially the basal layer, often with hyperconvoluted nuclei. Our findings support the hypothesis that CTCL develops sui generis, rather than from another chronic dermatosis.
Reassessment of histologic parameters in the diagnosis of mycosis fungoides
Smoller BR, etal.
Am J Surg Pathol 1995; 19: 1423.
Moderate disproportionate exocytosis combined with as few as one haloed lymphocyte per 20×field was 100% specific for MF
Histologic criteria for the diagnosis of mycosis fungoides: proposal for a grading system to standardize pathology reporting
Joan Guitart, etal.
J Cutan Pathol 2001;28 (4):174-183 Abstract quote
Background: The histological diagnosis of early lesions of mycosis fungoides (MF) is often difficult for dermatopathologists and prior studies have shown a low agreement rate among pathologists. An important reason for such difficulty may be the lack of specific histological criteria.
Methods: We tested a new method to interpret and report biopsies suspicious for MF. The method is based on a grading system reflecting the pathologist’s degree of diagnostic certainty. A panel of four pathologists independently assessed a set of 50 biopsies suspicious for MF first without (Phase I) and subsequently with specific histological criteria (Phase II). A third Phase was carried out after a training session, using a new set of cases with corresponding immunophenotyping and gene rearrangement analysis. Weighted and unweighted kappa statistics were used to assess inter- and intra-pathologist variation.
Results: The consensus rate among pathologists improved from 48% in Phase I to 76% in Phase III. Overall precision weighted kappas increased from 0.630 in Phase I to 0.854 in Phase III, indicating excellent inter-pathologist agreement by Phase III. There was a significant association between the presence of an abnormal phenotype and/or T-cell clonality and a higher diagnostic score.
Conclusions: The use of uniform criteria and training sessions can substantially improve the consensus rate among pathologists in the diagnosis of MF
Of cells and architecture: new approaches to old criteria in mycosis fungoides.
Glusac, Earl J.
Study summarizes key features regarding epidermotropism and cellular morphology Epidermotropism
J Cutan Pathol 2001;28 (4):169-173.
Recent studies have highlighted two important features of epidermotropic pattern: Pautrier’s microabscesses and the presence of lymphocytes within the epidermis which are larger than those within the dermis.
Lymphocytes within the epidermis which are larger than those within the dermis in approximately 20% of examples of MF15
Early MF, few neoplastic cells may be present in any given biopsy and in reality, the histologic features that are assessed are probably a reaction pattern to tumor
Pautrier’s microabcesses are found in 4 to 37% of cases
Epidermotropism associated with a paucity of spongiosis (disproportionate epidermotropism) may be found in approximately 58% of MF cases and approximately one quarter of controls.
Basilar epidermotropism (“a string of pearls” or “toy soldiers”) when it is defined as one to five basal lymphocytes per 20×field, was identified in more than two thirds of MF cases and fewer than a quarter of controls in one study
One study defined it as the presence of any four contiguous lymphocytes within the basal layer finding this be a specific but insensitive feature (93% specificity, 17% sensitivity for early MF).
Pagetoid spread, especially lymphocytes high in the epidermis may be more significant than basilar lymphocytes in some differentials.
Am J Surg Pathol 2000; 24: 40.
Am J Surg Pathol 1995; 19: 1423.
Medium-large cerebriform lymphocytes in the epidermis (lymphocytes 7–9 microns in diameter, approximating the width basal keratinocyte nuclei) in 24 of 24 biopsies of early mycosis fungoides and only 1 of 13 inflammatory mimics
Another study found convoluted nuclei in more than two thirds of examples of MF and fewer than one third of control cases
Mod Pathol 2001;14:285-288 Abstract quote
The manifestations of mycosis fungoides in its early stage may mimic clinically and histologically those of many benign inflammatory dermatoses. Therefore, the diagnosis of mycosis fungoides remains a major challenge for dermatologists and dermatopathologists. For many years, it has been proposed that atypical lymphocytes within the epidermis constitute one of the diagnostic features in mycosis fungoides. Presence of dermal atypical lymphocytes remains controversial as a diagnostic criterion.
We reassessed the feasibility of applying lymphocytic atypia within epidermis and dermis as diagnostic criteria discriminating between mycosis fungoides and spongiotic dermatitis.
Thirty cases of mycosis fungoides and 30 cases of spongiotic dermatitis were retrieved from archival hematoxylin and eosin-stained histologic sections. Punch biopsy sections were examined by light microscopy; epidermal and dermal lymphocytes were photographed at 1000x (oil immersion). A total of 92 ektachrome slides (35 mM) were developed, coded, and ordered randomly. For each slide, cells were interpreted as typical or atypical lymphocytes by seven pathologists. Atypical epidermal lymphocytes were judged to be present in 9 ± 2 out of 16 (56%) cases of mycosis fungoides photographed as compared with 8 ± 3 out of 16 (50%) in spongiotic dermatitis. Dermal lymphocytic atypia was thought to be present in 14 ± 6 out of 30 (47%) patients with mycosis fungoides. Thirteen ± 6 out of 30 (43%) patients with non-mycosis fungoides also displayed dermal lymphocytic atypia. No statistical significance was observed in these comparisons (t test, P > .05). Furthermore, atypia of lymphocytes was deemed to be present in 41, 38, 59, 70, 23, 47, and 40 out of 92 slides examined by the investigators, suggesting that observer variation is a very significant factor in our present study.
We conclude that it is not possible to distinguish mycosis fungoides from spongiotic dermatitis merely based on lymphocytic atypia within epidermis or dermis.
Am J Surg Pathol 1995; 19: 1423.
Am J Dermatopathol 1979; 1: 5.
Thought to result from artifactual contraction of the more abundant cytoplasm of neoplastic lymphocytes and are not typically identified in frozen sections
Best evaluated for in the upper epidermis rather than within the basal layer, where they may be confused with melanocytes.
Lymphocytes with a halo identifiable even at low magnification of “moderate degree” (1–5 per 20×field) in 59% of MF samples and 13% of patients biopsied to rule out MF who ultimately proved to have an inflammatory condition
Haloed lymphocytes were the best single discriminator of MF from inflammatory simulants
Papillary dermal fibrosis
Am J Surg Pathol 1995; 19: 1423.
Papillary dermal fibrosis alone has not been found to be a statistically significant discriminator between MF and MF-mimics
Feature is typical of late patch and of plaque stage MF but appears likely more indicative of chronicity than etiology
Am J Surg Pathol 1994; 18: 645.
Co-presence of eosinophils and plasma cells and regions of fine, dry parakeratosis, alternating with broader regions of orthokeratosis
Patch Sparse infiltrate of atypical lymphocytes with hyperconvoluted nuclei along the dermal-epidermal junction, epidermotropism with little spongiosis, Pautrier microabscesses, intraepithelial lymphocytes with clear perinuclear halos. Plaque Features of plaque stage but denser and more infiltrative Tumor Nodule composed of monomorphous atypical cells, often extending deeply into the fat VARIANTS BASALOID FOLLICULOLYMPHOID HYPERPLASIA
Basaloid folliculolymphoid hyperplasia with alopecia as an expression of mycosis fungoides (CTCL).
Kossard S, White A, Killingsworth M. S
kin and Cancer Foundation, Darlinghurst, NSW, Australia.
J Cutan Pathol 1995 Oct;22(5):466-71 Abstract quote
Follicular mucinosis, papules, cysts and comedones have been previously described as expressions of follicular involvement by mycosis fungoides.
We report a patient with mycosis fungoides who developed extensive alopecia. Multiple scalp biopsies showed perifollicular and intrafollicular infiltrate of lymphocytes but no evident follicular mucinosis.
On transverse sections many of the follicles showed an absence of differentiation towards hair sheath, canal, sebaceous gland or hair formation, but instead formed undifferentiated basaloid structures.
These basaloid structures showed transition from atrophic telogen follicles to hypertrophic basaloid islands infiltrated by lymphocytes, resembling the pattern previously described in cutaneous lymphadenoma. Immunophenotyping showed a predominance of helper T-cells which, on ultrastructural examination, showed cerebriform nuclei. The unusual histological findings in our case may be analogous to the hyperplasia seen in sweat glands in syringotropic mycosis fungoides (syringolymphoid hyperplasia), and we propose the term basaloid folliculolymphoid hyperplasia to describe this feature.
Basaloid follicular hyperplasia has been previously described as a component of follicular mucinosis but may apparently develop in the absence of overt mucinosis.
(WITH B-CELL CLL)
Am J Clin Pathol. 2006 Jul;126(1):14-22 Abstract quote.
Most cutaneous T-cell lymphomas are derived from mature postthymic T cells of the CD4 subtype. When other less common profiles are encountered, a diagnostic challenge is posed. Accurate categorization is critical because of the specificity of therapeutic regimens, including biologics.
A 65-year-old woman was seen in 2001 because of a thigh mass manifesting an unusual phenotype eventually categorized as a mature postthymic CD8+ T-cell lymphoma with CD10 and weak CD20 expression. Molecular studies revealed T-cell receptor and heavy chain immunoglobulin rearrangement. Her cutaneous disease progressed despite several cycles of chemotherapy and radiation therapy. However, a therapeutic trial with denileukin diftitox resulted in a striking response.
The importance of this case lies in the novel phenotype and dual T- and B-cell rearrangements. Rather than representing an aberrant phenotype, this tumor may represent the malignant counterpart of a benign population of weakly CD20+ T cells of the CD8 subset.
Composite mycosis fungoides and B-cell chronic lymphocytic leukemia.
Volk AL, Vannucci SA, Cook W, Thompson KA, Listinsky CM.
Departments of Pathology and Dermatology, The University of Alabama at Birmingham; and Alabama Oncology, Montgomery, AL.
Ann Diagn Pathol 2002 Jun;6(3):172-82 Abstract quote
Concordant or composite mycosis fungoides and B-cell chronic lymphocytic leukemia (B-CLL) is exceedingly rare, with only 10 cases previously described to our knowledge.
We report a case of a 64-year-old woman who developed generalized erythroderma 5 years after the diagnosis of early stage B-CLL. Over the next 6 years of her clinical course multiple sequential samples of skin, peripheral blood, and one enlarged lymph node were studied in detail by flow cytometry, immunohistochemistry, molecular diagnostics, and electron microscopy. The progressive cutaneous infiltrates were initially characterized as leukemia cutis, infiltration by B-CLL. Three years later, when she developed worsening skin disease and lymphadenopathy, the cutaneous infiltrates were characterized as cutaneous T-cell lymphoma. At that point, a biopsy of an enlarged lymph node revealed a composite lymphoma of both B-CLL and cutaneous T-cell lymphoma, and the peripheral blood also contained circulating cells of both neoplasms.
Herein we summarize the literature on concordant cutaneous T-cell lymphoma and B-CLL, and the literature on concordant T- and B-cell neoplasms in general, with a review of the postulated relationships between these neoplasms.
- In situ eosinophil activation in 26 primary cutaneous T-cell lymphomas with blood eosinophilia.
Ionescu MA, Rivet J, Daneshpouy M, Briere J, Morel P, Janin A.
Department of Dermatology, ERM 0220 INSERM/Hematology Institute IFR 105, Saint-Louis Hospital University Paris VII, France.
J Am Acad Dermatol. 2005 Jan;52(1):32-9. Abstract quote
Blood and tissue eosinophils can be associated with Hodgkin and non-Hodgkin lymphomas in that they have prognostic value. Tissue eosinophils in T-cell lymphoma patients with blood eosinophilia have not been systematically assessed. The objective of this research was to study the presence, density, and activation of tissue eosinophils in patients with primary cutaneous T-cell lymphomas (CTCLs) with blood eosinophilia and a possible relationship between features of the disease and prognosis.
With skin biopsy specimens from 26 CTCL patients with blood eosinophilia, tissue eosinophils were studied with electron microscopy, extracellular eosinophil peroxidase deposits, and interleukin-5 expression. Tissue eosinophils, found in 22 of 26 cases, were constantly activated. Both density and activation of tissue eosinophils were significantly related to disease progression.
The state of activation of tissue eosinophils in CTCL might reflect inflammatory flare-ups associated with aggressive lymphomas. Further studies are needed to confirm the value of eosinophil density as a simple and reliable marker of CTCL progression.
Fibromucinous T-cell lymphoma: a new clinicopathologic variant of mycosis fungoides?
Fairbee SI, Morgan MB, Tannenbaum MT, Glass LF.
University of South Florida College of Medicine, Division of Dermatology and Cutaneous Surgery and Pathology, Tampa, USA.
Am J Dermatopathol 2000 Dec;22(6):515-8 Abstract quote
We report a case of mycosis fungoides associated with extensive dermal fibrosis and mucin deposition.
The patient developed indurated plaques with diffuse tightening of the skin reminiscent of the sclerosing disorder scleromyxedema, which was later associated with nodules and lymphadenopathy. Skin biopsies showed diffusely thickened collagen bundles in the dermis and mucin deposition with a dense infiltrate of atypical lymphocytes with an immunophenotypic pattern indicative of mycosis fungoides.
In our opinion, these clinical and histopathologic features are unusual for mycosis fungoides and can be construed as a distinct fibromucinous variant. Alternatively, this may represent a fibrosing reaction pattern similar to that described with systemic T- and B-cell lymphomas or a variety of inflammatory disorders.
FOLLICULAR MYCOSIS FUNGOIDES
- Folliculotropic mycosis fungoides: an aggressive variant of cutaneous T-cell lymphoma.
Department of Dermatology, Northwestern University Feinberg School of Medicine, and The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
- Arch Dermatol. 2008 Jun;144(6):738-46 Abstract quote
OBJECTIVES: To study the clinical features, therapeutic responses, and outcomes in patients with folliculotropic mycosis fungoides (FMF) and to compare our single-center experience of 43 patients with the findings from the Dutch Cutaneous Lymphoma Group.
SETTING: A single-center experience from the Northwestern University Multidisciplinary Cutaneous Lymphoma Group.
PATIENTS: Forty-three patients with FMF were included in the study and compared with 43 age- and stage-matched patients with classic epidermotropic mycosis fungoides (MF) with similar follow-up time.
RESULTS: Folliculotropic mycosis fungoides showed distinct clinical features, with 37 patients having facial involvement (86%) and only 6 having lesions limited to the torso (14%). The morphologic spectrum of lesions is broad and includes erythematous papules and plaques with follicular prominence with or without alopecia; comedonal, acneiform, and cystic lesions; alopecic patches with or without scarring; and nodular and prurigolike lesions. Sixty-five percent of patients had alopecia, which in 71% of cases involved the face. Severe pruritus was seen in 68% of patients. In general, patients responded poorly to skin-directed therapy and in almost all cases required systemic agents to induce even a partial remission, including patients with early-stage disease. Overall survival was poor. Patients with early-stage disease (< or =IIA) had a 10-year survival of 82%, which took a steep drop off to 41% by 15 years. Patients with late-stage disease (> or =IIB) had an outcome similar to those patients in the control group with conventional epidermotropic MF of a similar stage.
CONCLUSIONS: The morphologic spectrum of clinical presentation for FMF is broad and distinct from those in conventional MF. This is at least partially attributed to the ability of FMF to simulate a variety of inflammatory conditions afflicting the follicular unit. The disease course is aggressive, and many patients, including those with early disease, show a poor outcome particularly between 10 and 15 years after the initial onset of disease. Response to skin-directed therapy is poor even in early-stage disease, and our best results were seen with psoralen plus UV-A (PUVA) therapy with oral bexarotene or PUVA with interferon alfa. These findings corroborate those of the Dutch Cutaneous Lymphoma Group and further validate the classification of FMF as a distinct entity.
- The spectrum of histopathologic and immunohistochemical findings in folliculotropic mycosis fungoides.
Northwestern University and The Feinberg School of Medicine, Chicago, IL.
- Am J Surg Pathol. 2007 Sep;31(9):1430-8. Abstract quote
BACKGROUND: Since the original designation of folliculotropic mycosis fungoides (FMF) as a distinct entity, there has been an increasing appreciation of the broad clinical and histopathologic spectrum with which this disease can present. However, there have been few large histologic studies characterizing the various histopathologic patterns.
OBJECTIVE: In this study, we attempt to describe the histopathologic and immunohistochemical features of 47 biopsy specimens from 34 patients with FMF.
METHODS: We searched our lymphoma database for patients with FMF in which detailed histopathologic information and slides as well as clinical information was available for review. Additionally, immunohistochemical studies for CD4, CD8, and CD1a were performed in all cases in which the block was available.
RESULTS: In addition to the prototypical pattern of a folliculotropic lypmphoid infiltrate with or without mucinosis, the histologic features of follicular mycosis fungoides may include a granulomatous reaction, cystic and comedonal changes, an eosinophilic folliculitis pattern and basaloid folliculolymphoid hyperplasia as well as pustular changes, interface dermatitis and an interstitial dermatitislike pattern. Unlike conventional mycosis fungoides, eosinophils and plasma cells are conspicuous within the accompanying reactive infiltrate. We have also noted an exceedingly high number of Langerhans cells within the follicular epithelium. The CD4:CD8 ratio frequently is 10:1 or greater and the follicles show abundant CD1a positive cells.
CONCLUSIONS: FMF may present with a broad spectrum of histopathologic changes including interstitial, granulomatous, fibrotic and acneiform reactions that may lack the typical histologic attributes of a cutaneous T-cell lymphoma. Recognition of these myriad of histologic presentations can be of great diagnostic utility.
- Pseudotumorous folliculotropic mycosis fungoides.
Kossard S, Weller P.
From the Skin and Cancer Foundation Australia, Sydney, Australia.
Am J Dermatopathol. 2005 Jun;27(3):224-7. Abstract quote
Fungating nodules and infiltrated plaques are usually equated with advanced tumor stage mycosis fungoides.
We report an 85-year-old man who presented in this way but multiple skin biopsies revealed that the bulk of his nodules were due to marked follicular hyperplasia as a result of folliculotropic mycosis fungoides. This clinical presentation may be best described as a pseudotumorous form of mycosis fungoides dominated by follicular epithelial hyperplasia rather than lymphocytic proliferation characteristic of true tumor stage disease.
Similar presentations have been described as a verrucous and hyperplastic variant of mycosis fungoides due to the presence of prominent epidermal hyperplasia.
Combined folliculotropic/syringotropic cutaneous T-cell lymphoma without epidermal involvement: report of 2 cases and pathogenic implications.
Jacobs MA, Kocher W, Murphy GF.
Jefferson Center for Dermatopathology and Division of Hematopathology, Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107-6799, USA.
Hum Pathol. 2003 Nov;34(11):1216-20 Abstract quote.
Exclusive involvement of skin appendages in cutaneous T-cell lymphoma (CTCL) is rare, poses significant problems in diagnosis, and may provide insight into mechanisms of T-cell epitheliotropism. We report 2 cases of combined adnexal (folliculotropic/syringotropic) CTCL in which lesions developed only in chronically sun-damaged skin.
Although the epidermal layer in both cases was devoid histologically of significant epidermotropism, immunohistochemistry and polymerase chain reaction analyses of deeper samples that included involved adnexae confirmed aberrant antigen expression (dominant CD4 populations with apparent loss of CD7 and/or CD5) and T cell clonality, respectively. It is diagnostically important to recognize adnexal CTCL as a disorder that may be clinically and histologically protean.
Additionally, its occurrence in sun-damaged skin in some patients may provide insight into mechanisms of selective epitheliotropism by malignant T cells.
Purely follicular mycosis fungoides without mucinosis: report of two cases with review of the literature.
Monopoli A, Annessi G, Lombardo GA, Baliva G, Girolomoni G.
Istituto Dermopatico dell'Immacolata, Istituto di ricovero e cura e carattere scientifico, Rome, Italy.
J Am Acad Dermatol 2003 Mar;48(3):448-52 Abstract quote
Follicular lesions can either associate with typical patch-/plaque-type mycosis fungoides or, more rarely, be the only clinical manifestation of the disease.
We describe 2 adult patients who presented with alopecia and disseminated follicular erythematous papules, and comedones and cysts, respectively. In both patients, histology showed a folliculotropic infiltrate of atypical lymphocytes that spared the epidermis, in the absence of follicular mucinosis.
Molecular genetic analysis confirmed the oligo/monoclonal nature of the T-cell infiltrate. Reported cases of purely follicular mycosis fungoides without mucinosis are reviewed.
Folliculotropic mycosis fungoides with central nervous system involvement: demonstration of tumor clonality in intrafollicular T cells using laser capture microdissection.
Ke MS, Kamath NV, Nihal M, Mikkola DL, Koc ON, Stevens SR, Gilliam AC, Cooper KD, Wood GS.
Department of Dermatology, Skin Diseases Research Center, Ireland Comprehensive Cancer Center, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH, USA.
J Am Acad Dermatol 2003 Feb;48(2):238-43 Abstract quote
BACKGROUND: Folliculotropic mycosis fungoides (MF) is a rare variant of cutaneous T-cell lymphoma, MF type, characterized by atypical lymphocytes preferentially infiltrating the hair-follicle epithelium relative to the epidermis.
OBSERVATIONS: We describe a rare case of folliculotropic MF involving the central nervous system. This is also the first case in which laser capture microdissection was used to show that the atypical lymphocytes within the hair-follicle epithelium were part of the same tumor clone present in other tissue compartments.
CONCLUSIONS: In reviewing the literature describing atypical lymphocytes infiltrating hair-follicle epithelium relative to the epidermis, we encourage the use of the term folliculotropic mycosis fungoides. Our case also supports previous findings that central nervous system involvement can occur in advanced MF. The successful procurement and analysis of atypical lymphocytes from hair-follicle epithelium by laser capture microscopy ushers in a new era in molecular diagnostics.
Folliculotropic mycosis fungoides with large-cell transformation presenting as dissecting cellulitis of the scalp.
Gilliam AC, Lessin SR, Wilson DM, Salhany KE.
Department of Dermatology, Case Western Reserve University, U.H.C. Cleveland, OH 44106, USA.
J Cutan Pathol 1997 Mar;24(3):169-75 Abstract quote
Follicular mycosis fungoides (MF) is a rare variant of cutaneous T-cell lymphoma (CTCL) in which malignant lymphocytes preferentially infiltrate hair follicles.
This report describes a patient with follicular mycosis fungoides presenting in a manner similar to dissecting cellulitis of the scalp with nonhealing, draining nodular lesions.
Follicular mucinosis associated with folliculotropic mycosis fungoides resulted in follicular disruption and deep dissecting cellulitis. Large-cell transformation of CTCL was present in the initial diagnostic scalp and axillary lymph node specimens. The patient died from progressive CTCL 9 months following initial diagnosis despite electron beam radiation, topical mechlorethamine, interferon-alpha, and systemic chemotherapy. This case indicates that large-cell transformation of folliculotropic mycosis fungoides is an aggressive form of CTCL, and that folliculotropic mycosis fungoides can give rise to lesions which resemble dissecting cellulitis of the scalp.
Upregulation of intercellular adhesion molecule-1 (ICAM-1) on follicular epithelium adjacent to lymphocyte function-associated antigen-1 (LFA-1)-positive folliculotropic lymphoma cells in this report provides insight into lymphocyte homing mechanisms in folliculotropic MF.
Follicular mycosis fungoides: a case report and review of the literature
James DeBloom II, etal.
Journal of Cutaneous Pathology 2001;28 (6):318-324 Abstract quote
Background: Follicular mycosis fungoides is an unusual variant of mycosis fungoides (MF). Unlike classic MF where atypical lymphocytes show a predilection for the epidermis (epidermotropism), follicular MF displays a malignant lymphocytic infiltrate tropic for hair follicles (folliculotropism). This malignant lymphocytic infiltrate results in follicular disruption typically manifesting clinically as plaques, comedones and follicular papules.
Methods: This report describes a 40-year-old patient with follicular MF presenting as nodules on the face and chest. Histologic examination of the patient’s biopsy revealed a folliculocentric infiltrate of atypical lymphocytes with sparing of the epidermis.
Results and Conclusions: Our case is discussed in the context of previously reported cases of follicular MF; we also include a review of all cases of follicular MF published to date that meet the strict criterion for this diagnosis.
Follicular mycosis fungoides. A histopathologic analysis of nine cases
Michael J. Flaig1, Lorenzo Cerroni2, Kathrin Schuhmann1, Hans Peter Bertsch1, Peter Kind1, Peter Kaudewitz1 and Christian A. Sander1
1Department of Dermatology, LMU, Munich, Germany, 2 Department of Dermatology, Graz, Austria
Journal of Cutaneous Pathology 2001;28 (10), 525-530 Abstract quote
Background: The spectrum of mycosis fungoides is exceedingly broad. Many different variants have been described, based on both clinical appearance and histological pattern. A rare form which shows preferential infiltration of hair follicles by malignant lymphocytes is follicular mycosis fungoides.
Methods: We reviewed our experience with nine cases of follicular mycosis fungoides.
Results: The unifying feature was infiltration of the hair follicle epithelium by atypical lymphocytes causing varying degrees of damage to the hair follicles. In some specimens the lymphocytes displayed only minor atypia leading to a misinterpretation as pseudolymphoma. Gene rearrangement studies were particularly helpful for establishing a diagnosis of malignant lymphoma. Additionally, epidermotropism of lymphocytes, eosinophils and mucin deposition were present to varying degrees. Mucin makes the distinction from mycosis fungoides-associated follicular mucinosis difficult. We found both dermal mucin and a follicular mucinosis pattern present at different stages of disease in the same patient.
Conclusions: We suggest the term mycosis fungoides-associated follicular mucinosis should be replaced by follicular mycosis fungoides in future lymphoma classification schemes.
Follicular Mycosis Fungoides, a Distinct Disease Entity With or Without Associated Follicular Mucinosis
A Clinicopathologic and Follow-up Study of 51 Patients
Remco van Doorn, MD; Erik Scheffer, MD; Rein Willemze, MD; for the Dutch Cutaneous Lymphoma Group
Arch Dermatol. 2002;138:191-198 Abstract quote
To determine the clinicopathologic features and the disease course of patients with follicular mycosis fungoides (MF).
A multicenter, 14-year, retrospective cohort analysis.
Dutch Cutaneous Lymphoma Group.
Fifty-one patients with the clinicopathologic features of follicular MF with (n = 49) or without (n = 2) associated follicular mucinosis. Follow-up data were compared with those of 158 patients with the classic epidermotropic type of MF, including 122 patients with generalized plaque-stage MF (T2 N0 M0) and 36 patients with tumor-stage MF (T3 N0 M0).
Characteristic clinical features not or rarely observed in classic MF were the preferential localization of the skin lesions in the head and neck region (45 of 51 patients), the presence of follicular papules, alopecia, acneiform lesions, mucinorrhoea, and often severe pruritus. Characteristic histologic findings were the presence of perifollicular neoplastic infiltrates with a variable degree of folliculotropism, but generally no epidermotropism, follicular mucinosis (49 of 51 cases), and often a considerable admixture of eosinophils and plasma cells. Response on initial treatment, risk of disease progression (development of extracutaneous disease and/or death from lymphoma), and disease-specific and overall survival of patients with follicular MF were worse than in classic MF patients. The actuarial disease-specific survival was 68% at 5 years and 26% at 10 years.
Follicular MF shows distinctive clinicopathologic features, is more refractory to treatment, and has a worse prognosis than the classic type of MF; it should be considered a distinct type of cutaneous T-cell lymphoma. Based on these results and those of other studies, we suggest the term follicular MF for cases with or without associated follicular mucinosis.
A case of follicular mycosis fungoides with follicular mucinosis: a rare association.
Campanati A, Giangiacomi M, Goteri G, Penna L, Turtu S, Offidani AM.
Am J Dermatopathol 2002 Oct;24(5):423-6 Abstract quote
Follicular mycosis fungoides (FMF) is a rare cutaneous T cell lymphoma characterized by an atypical lymphoid infiltrate spreading within and around hair follicles without epidermotropism or follicular mucin deposits. Its occasional presentation with minimal epidermal involvement and/or follicular mucinosis suggests the need for uniform histologic criteria.
We describe a new case of FMF associated with follicular mucinosis and discuss its morphologic spectrum of presentation.
Primary follicular mucinosis: Long-term follow-up of patients younger than 40 years with and without clonal T-cell receptor gene rearrangement.
Brown HA, Gibson LE, Pujol RM, Lust JA, Pittelkow MR.
Department of Dermatology and Section of Dermatopathology and Department of Medicine and Division of Hematology, Mayo Clinic, Rochester; and Hospital de la Santa Creu i Sant Pau, Barcelona.
J Am Acad Dermatol 2002 Dec;47(6):856-62 Abstract quote
Since the original descriptions of follicular mucinosis, accumulating experience shows that patient age, distribution of lesions, and duration or extent of disease do not reliably distinguish benign primary follicular mucinosis from secondary follicular mucinosis, associated with cutaneous lymphoma. More recently, it has been suggested that individuals with follicular mucinosis demonstrating a clonal T-cell receptor gene rearrangement may be at higher risk for the development of lymphoma.
Long-term follow-up of 7 patients younger than 40 years with primary follicular mucinosis are reported. In all cases, there was no clinical or histologic evidence of associated dermatoses or lymphoma at the time of diagnosis. Five of the patients have clonal T-cell gene rearrangement as determined by Southern blot analysis.
Clinically, at the time of diagnosis, lesions of primary follicular mucinosis ranged from papules confined to the face to widespread cutaneous plaques. After a mean follow-up of 10 years (range, 5-23 years) from the onset of disease, the majority of patients continue to have cutaneous manifestations of follicular mucinosis despite various treatments. There is no evidence of progression to cutaneous T-cell lymphoma in any patient despite the presence of a clonal T-cell receptor gene rearrangement.
Continued prolonged follow-up of patients with clonal primary follicular mucinosis is necessary to determine the significance of infiltrates harboring a T-cell receptor gene rearrangement. However, in our experience with this group of selected patients, primary follicular mucinosis has been a clonal disorder with limited or "benign" cutaneous manifestations.
Interstitial mycosis fungoides, a variant of mycosis fungoides resembling granuloma annulare and inflammatory morphea.
Su LD, Kim YH, LeBoit PE, Swetter SM, Kohler S.
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA, Department of Dermatology, Stanford University, Stanford, California, USA, Departments of Pathology and Dermatology, University of California, San Francisco, California, USA, and the Department of Pathology, Stanford University, Stanford, California, USA.
J Cutan Pathol 2002 Mar;29(3):135-141 Abstract quote
BACKGROUND:: Interstitial mycosis fungoides (IMF) is a rare variant of mycosis fungoides that resembles the interstitial form of granuloma annulare and inflammatory morphea. IMF has received little attention in the literature.
METHODS: Clinical, histological, immunophenotypical, and genotypical findings of five cases of IMF were reviewed. The histological and immunophenotypical findings were compared with those of eight cases of interstitial granuloma annulare and six cases of inflammatory morphea.
RESULTS: Five patients with IMF presented with non-indurated, erythematous macules; ill-defined erythematous plaques with slight scale; and nodules on the trunk and proximal limbs. Two of five patients had a prior diagnosis of mycosis fungoides. Skin biopsies revealed a striking dermal interstitial infiltrate of lymphocytes with rare histiocytes that resembled the interstitial form of granuloma annulare or inflammatory morphea. Epidermotropic lymphocytes were present at least focally in all cases. A band-like lymphocytic infiltrate was observed in two of five cases. In contrast, many plasma cells and histiocytes were observed in cases of inflammatory morphea and interstitial granuloma annulare, respectively. With Movat-pentachrome stains, increased dermal mucin deposition was observed in two of five IMF cases, in all cases of interstitial granuloma annulare, and in one of six cases of inflammatory morphea. There was focal loss of elastic fibers in all cases of inflammatory morphea. Immunohistochemical studies of IMF highlighted a dominant population of T cells (CD3+) in the dermis and epidermis. In contrast, moderate numbers of B cells (CD20+) were admixed with T cells and plasma cells in inflammatory morphea. Almost equal numbers of histiocytes (CD68+) and T cells comprised the infiltrate of interstitial granuloma annulare. In two of five IMF cases, a clonal T-cell population was detected by PCR T-cell gamma gene rearrangement analysis.
CONCLUSION: Mycosis fungoides occasionally presents as an interstitial lymphocytic infiltrate that mimics granuloma annulare and inflammatory morphea. Hematoxylin & eosin (H&E) findings alone can sometimes distinguish the three disorders. Immunophenotyping and genotyping may be helpful in difficult cases.
JUNCTIONAL 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.
LARGE PLAQUE PARAPSORIASIS
Large plaque parapsoriasis: clinical and genotypic correlations
MartinSimon, Michael J.Flaig, PeterKind, Christian A.Sander and PeterKaudewitz
J Cutan Pathol 2000;27 (2), 57-60 Abstract quote
Twelve patients with large plaque parapsoriasis (LPP) were investigated for the presence of predominant T-cell clones, analyzing the T-cell receptor (TCR) g-chain gene.
The diagnostic and prognostic significance of TCR gene rearrangement status was assessed by a correlation with the long-term clinical follow-up. Six out of 12 patients showed a clonal T-cell population. Clinically, among the patients with clonal disease one developed clearcut mycosis fungoides (MF) after a follow-up of 8 years, in the other 5 patients no such diagnosis could be made after follow-up of 2–21 years (median: 9 years). In patients with polyclonal infiltrates the lesions remained virtually unchanged. These findings indicate that in LPP TCR gene rearrangement status has no prognostic significance and does not allow distinction of LPP and early MF.
Both conditions show a clonal T-cell infiltrate with similar frequency, are very similar in clinical and histologic presentation and according to recent studies share the same low risk to develop overt MF. Therefore both terms refer to the identical clinical situation. This should be designated as early MF and efforts should concentrate on identifying those patients that are at risk to develop aggressive disease.
- Primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma: a cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance? A study of 136 cases.
Research Unit of Dermatopathology, Department of Dermatology, Medical University of Graz, Graz, Austria.
- Am J Dermatopathol. 2009 Jun;31(4):317-22. Abstract quote
Patients with skin nodules characterized by the infiltrate of pleomorphic small/medium T lymphocytes are currently classified as "primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma" (SMPTCL) or as T-cell pseudolymphoma. The distinction is often arbitrary, and patients with similar clinicopathologic features have been included in both groups.
We studied 136 patients (male:female = 1:1; median age: 53 years, age range: 3-90 years) with cutaneous lesions that could be classified as small-/medium-sized pleomorphic T-cell lymphoma according to current diagnostic criteria. All but 3 patients presented with solitary nodules located mostly on the head and neck area (75%).
Histopathologic features were characterized by nonepidermotropic, nodular, or diffuse infiltrates of small- to medium-sized pleomorphic T lymphocytes. A monoclonal rearrangement of the T-cell receptor-gamma gene was found in 60% of tested cases. Follow-up data available for 45 patients revealed that 41 of them were alive without lymphoma after a median time of 63 months (range: 1-357 months), whereas 4 were alive with cutaneous disease (range: 2-16 months).
The incongruity between the indolent clinical course and the worrying histopathologic and molecular features poses difficulties in classifying these cases unambiguously as benign or malignant, and it may be better to refer to them with a descriptive term such as "cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance," rather than forcing them into one or the other category. On the other hand, irrespective of the name given to these equivocal cutaneous lymphoid proliferations, published data support a nonaggressive therapeutic strategy, particularly for patients presenting with solitary lesions.
- Pleomorphic CD8+ Small/Medium Size Cutaneous T-Cell Lymphoma.
From the *Department of Dermatology, Rambam Medical Center and the Bruce Rappaport Faculty of Medicine, Technion, Institute of Technology, Haifa, Israel; daggerDepartment of Pathology, Rambam Medical Center and the Bruce Rappaport Faculty of Medicine, Technion, Institute of Technology, Haifa, Israel; and double daggerDepartment of Oncology, Rambam Medical Center and the Bruce Rappaport Faculty of Medicine, Technion, Institute of Technology, Haifa, Israel
- Am J Dermatopathol. 2006 Oct;28(5):434-437 Abstract quote
Pleomorphic small/medium-sized cutaneous T-cell lymphoma is a recently recognized rare type of cutaneous T-cell lymphoma which is clinicopathologically different from mycosis fungoides and Sezary syndrome.
By definition the phenotype of the neoplastic lymphocytes in pleomorphic small/medium-sized cutaneous CD3CD4CD8 but CD8 pleomorphic small/medium sized cutaneous T-cell lymphoma cases have been occasionally described.
We describe a 55-year-old female with a pruritic erythematous nodule on the lateral aspect of her right foot present for 1.5 years. Histology revealed a nonepidermotropic lichenoid infiltrate in the papillary dermis and a patchy infiltrate in the mid and lower dermis composed of small to medium-sized pleomorphic lymphocytes. The immunophenotype of these lymphocytes was CD3CD4CD8TIA-1. Staining for CD20, CD30, CD56, TdT, and LMP1 were negative, and the Ki-67 proliferation index was 5% to 10%. Gene rearrangement studies demonstrated a T-cell clone.
The laboratory and imaging workup did not reveal extracutaneous involvement. The lesion was treated by local irradiation but a follow-up biopsy demonstrated only partial remission. Consequently, the lesion was treated by surgical excision.
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.
Malignant lymphoma presenting as pseudoepitheliomatous hyperplasia. A report of two cases.
Krasne DL, Warnke RA, Weiss LM.
Department of Pathology, Stanford University, CA 94305.
Am J Surg Pathol 1988 Nov;12(11):835-42 Abstract quote
The authors report two patients with cutaneous and submucosal non-Hodgkin's lymphoma of probable T-cell phenotype that presented as florid pseudoepitheliomatous hyperplasia.
The first patient presented with lesions of the nasopharynx and nose that were originally misdiagnosed as invasive squamous cell carcinoma, causing a delay in appropriate treatment. In the second patient, skin lesions of the thigh and arm closely mimicked squamous cell carcinoma.
To prevent misdiagnosis of these lesions, pathologists should adhere to strict morphologic criteria for the diagnosis of squamous cell carcinoma and be aware that malignant lymphoma may be associated with overlying pseudoepitheliomatous hyperplasia. The pathogenesis of pseudoepitheliomatous hyperplasia arising in association with neoplasms is still not clear, but it may be related to the production of cellular growth factors by the inciting tumor.
CHARACTERIZATION Special stains Immunoperoxidase
Adv Dermatol 1996;11:255-284
Most common immunophenotypic profile is:
CD3, CD4, CD45RO positive
CD8, CD30 negative
Cells most commonly show anomalous of CD7 followed in frequency by loss of CD2, CD5, or CD3
- J Am Acad Dermatol. 2006 Aug;55(2):276-84. Abstract quote
BACKGROUND: Mycosis fungoides (MF) is an epidermotropic cutaneous T-cell lymphoma in which the tumor cells express a mature T-helper memory phenotype, ie, CD3(+), CD4(+), CD8(-), CD45RO(+), with a T-cell receptor (TCR) of the alpha/beta heterodimer. A minority of patients have an unusual immunohistochemical profile consisting of a CD4(-), CD8(+) mature T-cell phenotype. An aberrant CD4/CD8 double-negative (DN) immunophenotype in patients with early MF has rarely been reported.
OBJECTIVES: We sought to evaluate the frequency of CD4/CD8 DN immunophenotype in patients with early MF, and to study their clinical, histopathologic, and immunohistochemical features, and the course of their disease.
METHODS: Our departmental archives were searched for patients with early-stage MF and CD4/CD8 DN immunophenotpye.
RESULTS: Of the 140 patients with early MF immunophenotyped in our laboratory, 18 (12%) showed CD4 and CD8 expression in less than 10% of their intraepidermal T cells on fresh-frozen and paraffin-embedded samples. The group included 13 male and 5 female patients; 14 adults and 4 children; and 15 Jews and 3 Arabs. In all, 8 had classic MF and 10 had unusual clinical variants (5 hypopigmented, 3 localized, 1 ichthyosiform, 1 purpuric). All received skin-targeted therapies and all had an indolent course (mean follow-up 3.5 years). Histopathology revealed early MF. Results of immunohistochemical analysis of the intraepidermal lymphocytes were as follows: CD3(+), CD4(-), CD8(-) in all patients; CD7(-) in all of 17; CD45RO(+) in 15 of 16; T-cell-restricted intracellular antigen-1(+) in 11 of 15; CD30(+) in 2 of 16; and CD56(+) in 2 of 16. A betaF1(+)/delta(-) phenotype, indicating a TCR of the alpha/beta heterodimer, was found in 8 of 16; betaF1(-)/delta(+) phenotype, indicating a TCR of the gamma/delta heterodimer, in 1 of 16; betaF1(-)/ delta(-) in 5 of 16; and no determinable phenotype in 2 of 16. The TCR gamma gene was clonally rearranged in 10 of 16 patients.
LIMITATION: This was a single-center case series.
CONCLUSIONS: There is a subgroup of patients with e
arly MF that exhibit a CD4/CD8 DN immunophenotype. In our region, this aberrant immunophenotype is not as rare as reflected in the literature, is overrepresented in the unusual clinical variants of MF, and does not seem to have prognostic significance. Like CD4(+) MF, the tumor cells represent memory T cells and in many cases express alpha/beta TCR, but unlike CD4(+) MF, they have a mostly cytotoxic phenotype. We suggest that CD4/CD8 DN MF should be recognized as another immunohistochemical variant of this lymphoma.
Usefulness (or Lack Thereof) of Immunophenotyping in Atypical Cutaneous T-Cell Infiltrates
Scott R. Florell, MD, etal
Am J Clin Pathol 2006;125:727-736Abstract quote
Our purpose was to evaluate the interobserver concordance for the diagnoses of mycosis fungoides (MF), atypical dermatoses (AD), and benign dermatoses (BD) and the impact of T-cell immunophenotyping on the diagnoses MF, AD, and BD.
Specimens of MF (n = 57), AD (n = 27), and BD and normal skin (n = 54) were reviewed by 2 hematopathologists and 1 dermatopathologist to establish diagnostic interobserver concordance by routine morphologic examination. Immunophenotyping was performed to evaluate expression of CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, and MIB-1.The interobserver concordance was fair to moderate compared with the original diagnosis. Partial deletion of CD2 alone was associated significantly with MF. Epidermal deletions of 2 or 3 T-cell antigens or 2 T-cell antigens not including CD7 were associated significantly with MF. An elevated CD4/CD8 ratio correlated with MF. Morphologic features were most diagnostic of MF.
Immunophenotyping generally resulted in downgrading of the reaction pattern but was helpful in distinguishing MF from benign dermatoses.
Anomalous acquisition of CD22 B-cell surface marker Mod Pathol 1999;12:177-199
If this is present, this is also suggestive of T-cell malignancy
- Cluster designation 5 staining of normal and non-lymphoid neoplastic skin
Bogner PN, Su LD, Fullen DR.
Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI, USA.
J Cutan Pathol. 2005 Jan;32(1):50-4. Abstract quote
Background: Immunohistochemical staining for cluster designation 5 (CD5) has been found to label a variety of non-lymphoid tumors.
Methods: A variety of eccrine, apocrine, follicular, epithelial, and pagetoid lesions were selected and stained with an anti-CD5 monoclonal antibody (Novocastra Labs, Newcastle upon Tyne, UK, clone 4C7) by immunohistochemistry. The intensity of positive cytoplasmic staining was graded semiquantitatively (1+ weak staining, 2+ strong staining). Additionally, the percentage of positive lesional cells was placed in one of four categories: >75%, 25-75%, 1-25%, and <1%.
Results: Within normal skin, CD5 labeled lymphocytes, apocrine glands, deep dermal eccrine glands, and smooth muscle (weak). The majority of benign and malignant apocrine lesions demonstrated strong focal (36%, n = 11)-to-diffuse (64%, n = 16) staining. In contrast, labeling of benign eccrine tumors was more focal, tending to localize around ducts (79%, n = 19). Microcystic adnexal carcinoma demonstrated focal staining of deeper ductal structures (71%, n = 7), whereas desmoplastic trichoepithelioma and basal cell carcinoma showed only rare positive cells. All cases of mammary (n = 7) and extramammary (n = 8) Paget's disease labeled diffusely for CD5. Pagetoid Bowen's disease (n = 6), intraepidermal sebaceous carcinoma (n = 3), nor melanoma in situ (n = 6) showed any CD5 staining.
Conclusions: Immunohistochemical staining for CD5 is extremely useful in the differential diagnosis of pagetoid epidermal lesions and will mark mammary and extramammary Paget's disease, but not pagetoid Bowen's disease, melanoma in situ, or sebaceous carcinoma.
Evaluation of a new paraffin-reactive CD7 T-cell deletion marker and a polymerase chain reaction-based T-cell receptor gene rearrangement assay: Implications for diagnosis of mycosis fungoides in community clinical practice
Adrian Ormsby, MBChB Wilma F. Bergfeld, MD, Raymond R. Tubbs, DO, Eric D. Hsi, MD
J Am Acad Dermatol 2001;45:405-13 Abstract quote
Background: T-cell deletion and T-cell receptor (TCR) gene rearrangement studies are helpful in the early diagnosis and subsequent management of mycosis fungoides (MF). However, this often requires fresh-frozen tissue that can be difficult to obtain and evaluate in community clinical practice. A new CD7 antibody, the most sensitive and specific T-cell deletion marker, and a new TCR- gene rearrangement polymerase chain reaction (PCR) assay (TCR- PCR) are now available on routine paraffin-embedded biopsy specimens.
Objective: Our purpose was to assess the utility of CD7 deletion and TCR- PCR in the diagnosis of MF using routine paraffin-embedded biopsy material.
Methods: Cases of MF (n = 17) with matching frozen tissue immunohistochemistry and benign reactive dermatoses (lichen planus; n = 27) were assessed for CD7 (Clone: CD7-272) deletion and TCR- PCR using paraffin-embedded biopsy specimens.
Results: Excellent concordance comparing frozen and paraffin embedded CD7 immunostaining (88%) was observed. CD7 deletion and TCR- PCR was sensitive (94%) and specific (96%) for a diagnosis of MF using paraffin-embedded biopsy specimens.
Conclusion: In the diagnosis of MF, detection of CD7 deletion and monoclonal TCR rearrangements can be successfully performed in a cost-effective, timely fashion using routine formalin-fixed paraffin-embedded biopsy specimens.
Low CD7 expression in benign and malignant cutaneous lymphocytic infiltrates: experience with an antibody reactive with paraffin-embedded tissue.
Murphy M, Fullen D, Carlson JA.
Department of Dermatology, University of Connecticut Health Center, Farmington, Connecticut, USA.
Am J Dermatopathol 2002 Feb;24(1):6-16 Abstract quote
Loss of CD7 expression by neoplastic lymphocytes is considered a distinguishing characteristic of mycosis fungoides (MF) and cutaneous T-cell lymphoma. Reports to date examining for the CD7 immunophenotype in MF have been performed on fresh-frozen tissue.
In this study, we used a paraffin-reactive antibody directed against CD7 to determine its range of expression in MF and to compare these results with those in controls. Examining 22 cases of MF and 61 controls, we found minimal CD7 expression by lymphocytes in MF and in a few cases of benign inflammatory dermatosis (BID). The lowest mean CD7 counts (as a percentage of total lymphocytes) were found in MF (patch stage: 5% +/- 5%, range: 0-10; plaque and tumor stages: 15% +/- 5%, range: 5-25), and these counts were significantly lower than those for BID (35% +/- 20%, range: 5-80; p = 0.001).
By logistic regression analysis, low CD7 expression (<10% lymphocytes labeling) had sensitivity and positive predictive values of 80% and 72%, respectively, and specificity and negative predictive values of 93% and 96%, respectively, for the diagnosis of patch stage MF. False-positive results were found for spongiotic dermatitis. Moreover, spongiotic dermatitides exhibited a progressive decrease in mean CD7 counts from acute to subacute to chronic stages (50% versus 35% versus 30%, respectively).
In conclusion, minimal CD7 expression is a specific finding for MF. Benign inflammatory infiltrates can also show low CD7 expression, however, which rarely matches that of patch stage MF. Progressive loss of CD7 expression in BID is the likely consequence of expansion of antigen-selected CD3+CD4+CD7- T cells. These inflammatory CD4+CD7- T cells may represent the physiologic counterpart to the neoplastic lymphocyte of MF.
- CD20 positive mycosis fungoides: a case report.
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
- J Cutan Pathol. 2008 Apr;35(4):398-403. Abstract quote
CD20 positive T-cell lymphoma is extremely rare. Most reported cases are nodal peripheral T-cell lymphomas (PTCLs) or rarely lymphoma involving extranodal sites. Only two cases of CD20 positive T-cell lymphomas involving the skin have been previously reported and were classified as PTCL - not otherwise specified.
We present a case report of a 53-year-old man with CD20 positive mycosis fungoides (MF) involving the skin and an inguinal lymph node. The patient presented with erythematous patches and plaques of the right lower extremity and was found to have an enlarged inguinal lymph node 2 years later. Flow cytometric immunophenotyping of the lymph node aspirate showed a CD2+/CD3+/CD4+/CD5+/CD7-/CD8- T-cell population with CD20 co-expression. Molecular studies by polymerase chain reaction demonstrated clonal T-cell receptor gamma chain gene rearrangement. Immunoglobulin heavy and light chain gene rearrangements were not identified.
To our knowledge, this is the first case of CD20 positive MF involving a lymph node to be reported in the literature.
HEMATODERMIC NEOPLASMS CD4+ CD56+
- CD4+, CD56+ mycosis fungoides: case report and review of the literature.
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
- Am J Dermatopathol. 2009 Feb;31(1):74-6. Abstract quote
This case report details an 85-year-old woman who presented with mycosis fungoides (MF), clinical stage 1A. Bilateral lesions on the upper thighs were responsive to topical steroid therapy. Biopsies showed band-like dermal infiltrates of medium-sized lymphocytes with marked epidermotropism, including large intraepidermal lymphocytes with nuclear convolutions, consistent with MF. Immunohistochemical staining revealed that the lesional cells were CD56+, but unlike the case in previous reports of CD56+ MF, they also expressed CD4 and T-cell intracellular antigen 1 and did not express CD8.
To our knowledge, this is the first description of a case of MF with a CD4+, CD8-, CD56+, T-cell intracellular antigen 1-positive immunophenotype. At 85 years of age, the patient is older than all previously described patients with CD56+ MF.
Despite an immunophenotype observed more commonly in aggressive forms of cutaneous T-cell lymphoma, the clinical presentation is that of typical MF. The patient presented with limited disease and after 12 months of follow-up has not progressed beyond stage 1A.
- CD4+/CD56+ hematodermic neoplasm: report of a rare variant with a T-cell receptor gene rearrangement.
Department of Pathology, University of Washington, Seattle, WA 98195-6100, USA.
- J Cutan Pathol. 2008 Jun;35(6):579-84. Abstract quote
CD4+/CD56+ hematodermic neoplasm (HN), formerly known as a blastic natural killer (NK) cell lymphoma, is a rare subtype of a cutaneous dendritic cell neoplasm notable for highly aggressive behavior.
The characteristic features are: expression of the T-helper/inducer cell marker CD4 and the NK-cell marker CD56 in the absence of other T cell or NK-cell specific markers. In particular, CD3 (surface or cytoplasmic) and CD2 are not expressed.
Although T-cell receptor (TCR) genes are generally reported to be in a germline configuration, we present an unusual variant of a CD4+/CD56+ HN with a clonal rearrangement of TCR genes. This feature of a CD4+/CD56+ HN has been only rarely reported. Recognition of the presence of clonal TCR gene rearrangements in a small subset of CD4+/CD56+ HN is important to avoid misdiagnosis of this entity as an unusual variant of a cutaneous T-cell lymphoma.
J Am Acad Dermatol. 2005 Jul;53(1):158-63. Abstract quote
We report 3 cases of mycosis fungoides (MF) with a CD56+ cytotoxic immunophenotype.
Each patient presented with a different clinical phenotype: one exhibited limited poikilodermatous patches (skin stage T1); one, widespread hypopigmented lesions (skin stage T2); and one, poikiloderma with a single cutaneous tumor (skin stage T3).
MF was confirmed both histologically and by the presence of a T-cell receptor clone in lesional skin in all cases. CD56 and T-cell intracellular antigen-1 were expressed by the malignant lymphocytes in all patients and two expressed CD8. No sample demonstrated loss of the pan T-cell markers CD2 or CD3.
None of the 3 developed systemic disease and T-cell receptor gene analysis of peripheral blood was polyclonal in all cases. Only 3 cases of CD56+ MF have been reported previously, none of which exhibited tumor-stage disease.
Currently, the disease in our patients appears to be behaving in a manner similar to that predicted for MF with a normal immunophenotype but the prognosis has to be guarded in view of the rarity of this subtype.
Hum Pathol. 2005 Sep;36(9):1020-4. Abstract quote
CD4(+)CD56(+) hematodermic neoplasms (HNs) with initial presentation in the skin are characterized by highly aggressive behavior and poor prognosis. Recent studies indicate that malignant cells, which are devoid of common T-, B-, NK-, and myeloid lineage markers, may be of plasmacytoid dendritic cell (pDC) origin.
We undertook a study to assess the expression of several pDC-associated molecules on a series of 5 CD4(+)CD56(+) HN cases. CD123 was expressed in all 5 cases, with some heterogeneity in individual cases. All but one case revealed fine membranous BDCA-2 staining of the dermal infiltrate. pDC-like phenotype of the malignant infiltrating cells was confirmed by costaining of BDCA-2(+) cells with CD123 and CD4. MxA protein, representing the surrogate marker for lesional type I interferon activity, was expressed in 4 of 5 evaluated cases.
Our findings further substantiate the putative pDC origin of CD4(+)CD56(+) HNs.
- The application of a monoclonal antibody to CD62L on paraffin-embedded tissue samples in the assessment of the cutaneous T-cell infiltrates.
Magro CM, Sachdeva MP, Crowson AN, Barusevicius A, Baran PN, Kovatich AJ.
Department of Pathology, The Ohio State University, Columbus, OH, USA.
J Cutan Pathol. 2005 Jan;32(1):12-20. Abstract quote
Background: A reduction in the expression of the pan T-cell markers CD7 and CD62L supports an endogenous T-cell dyscrasia. Previously, clone availability for CD62L restricted its application to frozen tissue sections.
Materials and methods: A nonavidin/biotin technique to examine CD3, CD62L, and CD7 in paraffin formalin-fixed tissue in non-neoplastic and neoplastic T-cell infiltrates.
Results: In the reactive group, CD62L manifested a 15 and 22% reduction in epidermal and dermal staining, respectively; there was a 42 and 31% reduction in epidermal and dermal CD7 staining. In lymphomatoid hypersensitivity, CD62L showed a 24 and 9% reduction in epidermal and dermal staining, respectively; CD7 staining demonstrated reduced staining by 70 and 66% in the epidermis and dermis. In the non-lymphomatous endogenous T-cell dyscrasia and lymphoma categories, an 80% diminution in CD62L and CD7 expression was seen.
Conclusions: CD62L can be successfully applied in formalin-fixed tissue and exhibits enhanced specificity compared to CD7 in the evaluation of cutaneous T-cell infiltrates. Both CD62L and CD7 in paraffin-embedded, formalin-fixed tissue are useful diagnostic adjuncts, especially in regard to the discrimination of lymphomatoid hypersensitivity reactions from true endogenous T-cell dyscrasia.
c-kit (CD117) C-KIT expression in primary cutaneous T-cell lymphomas.
Brauns TC, Schultewolter T, Dissemond J, Maschke J, Goos M.
Department of Dermatology, Venereology, and Allergology, University of Essen, Essen, Germany.
J Cutan Pathol. 2004 Oct;31(9):577-82. Abstract quote
Background: Mutations of the stem cell factor receptor C-KIT play a major pathogenetic role in the development of different malignant diseases like human mastocytosis, myeloproliferative disorders, gastrointestinal stromal tumors, acute myelogenous leukemia, and sinonasal lymphomas. Furthermore, the expression of C-KIT has been described in Hodgkin's disease and nodal CD30(+) anaplastic large cell lymphomas (ALCLs). As it is possible to inhibit C-KIT by innovative kinase inhibitors like STI571, it may be an attractive target for new therapeutical approaches. Therefore, we screened more than 50 different types of cutaneous T-cell lymphomas (TCLs) for the presence of C-KIT. Immunohistochemical stainings were performed on paraffin-embedded tissue sections using a polyclonal rabbit anti-human C-KIT antibody. Naphtol-ASD-chloroacetate esterase (NASDCE)-control stainings were performed on every positive sample to distinguish C-KIT-positive lymphoma cells from C-KIT-positive mast cells.
Results: We found weak expression of C-KIT in seven of 18 patients with primary cutaneous CD30(+) ALCL, two of eight patients with primary cutaneous pleomorphic TCL, six of 18 patients suffering from mycosis fungoides, and three of five patients with Sezary's syndrome. Generally, only a very small population of the lymphoma cells expressed C-KIT. This finding indicates a difference to the systemic variant of CD30(+) ALCL. The potential use of C-KIT targeting new therapeutical approaches is therefore discussed critically, because C-KIT expression is very rare in all investigated types of primary cutaneous lymphoma.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES GENERAL
- Histologic mimickers of mycosis fungoides: a review.
Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, MA, USA.
- J Cutan Pathol. 2007 Jul;34(7):519-25. Abstract quote
Mycosis fungoides (MF) is a rare type of non-Hodgkin's lymphoma affecting the skin. Because MF develops slowly over several years and may have a variety of clinical presentations, including itchy patches, plaques or tumors that may be confused with common benign conditions such as eczema and psoriasis, the disease presents a diagnostic challenge.
The average time to diagnosis varies but is frequently as long as 3 to 6 years. Skin biopsies frequently reveal non-specific features of several dermatoses; thus, histologic evaluation of the disease is also challenging. Importantly, various significant and/or benign conditions may mimic MF histologically and result in a misdiagnosis of MF.
Here we review the reported histologic mimickers of MF and discuss both similar and differentiating features of each, in order to aid in more accurate interpretation of diagnostically challenging skin biopsies. Clinicopathologic correlation is ultimately essential to make accurate diagnosis of MF and its histologic mimickers.
Mycosis fungoides: The great imitator.
Zackheim HS, McCalmont TH.
Departments of Dermatology and Pathology, University of California, San Francisco.
J Am Acad Dermatol 2002 Dec;47(6):914-8 Abstract quote
A considerable number of reports have documented mycosis fungoides (MF) mimicking other dermatoses, but a comprehensive review has not been published. Our aim was to comprehensively review reports of various dermatoses simulated by MF.
Additionally, 2 cases in which MF simulated diseases not previously documented (psoriasis and erythema annulare centrifugum) are presented. A literature search of all case reports of MF cited in the MEDLINE database from 1966 through 2000 plus those in one of the author's (H. Z.) files was performed. A total of 23 reported cases of dermatoses mimicked by MF were found.
With the additional 2 dermatoses now presented, this yields a total of at least 25 diseases that can be simulated by MF. In view of the considerable number of dermatoses simulated by MF, the term the great imitator is appropriate for MF.
ADULT T-CELL LEUKEMIA/LYMPHOMA
Comparative study of cutaneous T-cell lymphoma and adult T-cell leukemia/lymphoma.
Nagatani T, Miyazawa M, Matsuzaki T, Iemoto G, Kim ST, Baba N, Miyamoto H, Nakajima H.
Department of Dermatology, Yokohama City University School of Medicine, Japan.
Semin Dermatol 1994 Sep;13(3):216-22 Abstract quote
An important disease entity distinct from cutaneous T-cell lymphoma (CTCL) in Japan is adult T-cell leukemia/lymphoma (ATL), which shows almost the same phenotype as CTCL, ie, a helper/inducer T-cell phenotype (CD4-positive, CD8-negative), and usually involves the skin.
This article describes differences between CTCL and ATL in terms of clinical and immunopathologic cell surface features. In patients with ATL, the predominant physical findings were lymph node, bone marrow and skin involvement, hepatosplenomegaly, leukemic manifestations, and an aggressive course. In patients with CTCL, in contrast, only skin lesions predominated at the onset of the disease and a relatively good prognosis was shown.
The predominant phenotype of the neoplastic cells in the skin of patients with CTCL was CD3+, CD4+, CD29+, CD45RO+, HLA-DR+, HLA-DQ+, CD7-, L-selectin-, and CD45RA-. Some phenotypic discrepancy was found between the neoplastic cells in the peripheral blood, lymph nodes and skin of patients with ATL with respect to CD45RA and CD45RO, and CD7, CD29, CD25, and HLA-DR. That is, the predominant neoplastic cell phenotype was helper T-cell, which was CD3+, CD4+, L-selectin+, CD25+, CD45RA+, HLA-DR+, CD29-, and CD45RO- in peripheral blood, and CD3+, CD4+, L-selectin+, CD29+, CD45RO+, HLA-DR+, and CD45RA- in the skin and lymph nodes. Phenotypic heterogeneity of ATL cells and heterogeneity of CD45R isoform expression on ATL cells were evident in different organs.
These findings confirm that the difference in antigen expression on the cell surface might reflect the clinical features of ATL and CTCL. CTCL cells do not share the same phenotype as ATL cells.
CHRONIC ACTINIC DERMATITIS
Chronic actinic dermatitis. An immunohistochemical study of its T-cell antigenic profile, with comparison to cutaneous T-cell lymphoma.
Heller P, Wieczorek R, Waldo E, Meola T, Buchness MR, Soter NA, Lim HW.
Pathology and Laboratory Medicine Services, New York Department of Veterans Affairs Medical Center, NY 10010.
Am J Dermatopathol 1994 Oct;16(5):510-6 Abstract quote
Chronic actinic dermatitis (CAD) describes a persistent photosensitivity disorder in the absence of continued exposure to photosensitizers; it is characterized by a T-cell infiltrate within the epidermis and dermis.
The purpose of this study was to characterize the T-cell infiltrate better immunohistochemically. Serial cryostat sections of fresh-frozen punch biopsy specimens of skin were analyzed in 11 patients with CAD and 3 patients with erythrodermic cutaneous T-cell lymphoma (CTCL). Monoclonal antibodies against the pan T-cell, pan B-cell, and T-cell subsets and the T cell-receptor (TCR) antigens were used. CD8-positive (T-suppressor-cytotoxic) cells were predominant in the epidermis of CAD, while CD4-positive (T-helper) cells were predominant in the epidermis and dermis of CTCL. CDw29-positive (T-memory) cells were predominant in all cases.
The number of BF1 (beta-chain constant region of the TCR)-positive cells approximated the number of CD3-positive cells in all CAD cases but was significantly lower than the number of CD3-positive cells in two of three cases of CTCL. There was no clustering or preferential staining with any of the beta-chain variable-region antibodies in any of the specimens.
These results indicate that CAD has a characteristic immunophenotype distinct from that of most cases of CTCL and that discordance between BF1 and CD3 expressions did not occur in the CAD cases.
Mycosis fungoides-like reaction in a patient treated with Gleevec.
Clark SH, Duvic M, Prietol VG.
Departments of Pathology and Medicine (Dermatology), The University of Texas - MD Anderson Cancer Center, Houston, TX, USA
J Cutan Pathol 2003 Apr;30(4):279-81 Abstract quote
BACKGROUND: Gleevec trade mark is a protein tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumor. Currently, Gleevec is also being used in protocols for treatment of other malignancies such as melanoma. A few, non-descript cutaneous eruptions have been reported in patients receiving Gleevec.
CASE REPORT: A patient with a gastrointestinal stromal tumor developed a centripetal, slightly pruritic, predominantly macular eruption. Histologically, there was a superficial and mid-perivascular cellular infiltrate of hyperchromatic, large lymphocytes with focal epidermotropism, thus resembling mycosis fungoides. The infiltrate was composed predominantly of T cells (CD3), with a 1:1 CD4:CD8 ratio, therefore consistent with a reactive process, i.e. a drug reaction induced by Gleevec.
CONCLUSION: Gleevec should be considered in the differential diagnosis of pseudolymphoma drug eruptions.
LANGERHANS CELL MICROGRANULOMAS
Langerhans cell microgranulomas (pseudo-pautrier abscesses): morphologic diversity, diagnostic implications and pathogenetic mechanisms.
Burkert KL, Huhn K, Whitaker Menezes D, Murphy GF.
The center for Dermatopathology, Departments of Pathology and Dermatology, Jefferson Medical College, Philadelphia, PA, USA, Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD, USA
J Cutan Pathol 2002 Oct;29(9):511-6 Abstract quote
The term 'Langerhans cell microgranuloma' (LCM) was introduced a decade ago to draw attention to focal collections of these cells within the epidermal layer that develops during certain immune reactions. In spite of a growing awareness of this phenomenon during the past decade, few reports have focused on the development and phenotype of LCM.
In this commentary, we review the historical development of the concept of LCM, demonstrate the salient immunomorphologic characteristics of LCM, and advance a hypothesis to explain their sequential evolution and formation.
Benign lichenoid keratoses with histologic features of mycosis fungoides: clinicopathologic description of a clinically significant histologic pattern.
Al-Hoqail IA, Crawford RI.
Department of Dermatology, King Khalid University Hospital and Faculty of Medicine at King Saud University, Riyadh, Saudi Arabia, Division of Dermatology and Department of Pathology, University of British Columbia, Vancouver, Canada.
J Cutan Pathol 2002 May;29(5):291-4 Abstract quote
Background: Benign lichenoid keratosis (BLK) is a well-known clinicopathologic entity and several histopathologic patterns havebeen described. Features mimicking mycosis fungoides (MF) in clinically typical BLKs have not yet been emphasized. The aim of this study was to confirm the occurrence of an MF-like pattern of BLK.
Methods: A retrospective survey was conducted on cases diagnosed as BLK over a 9-month period in a regional dermatopathology service. Seven histologic parameters, previously confirmed as diagnostically suggestive of MF, were applied. Inclusion criteria were: three or more MF-related histologic features and a size less than 2 cm. The clinical features were reviewed.
Results: Fifteen cases of MF-pattern BLK were identified. The number of MF-like parameters present in individual cases exceeded the inclusion criteria by variable amounts. Pautrier microabscesses and alignment of lymphocytes along the basal layer were the most frequent (14/15). The age of the patients ranged from 28 to 83 years, with a mean of 50. The size of the lesions ranged from 0.2 to 1.8 cm, with a mean of 0.6 cm. The upper trunk was the favored site. Most of the lesions had been removed because of suspicion of cutaneous malignancy; basal cell carcinoma was the most frequent clinical diagnosis.
Conclusion: We describe an MF-like histologic pattern of BLK. Pathologists and dermatopathologists should be aware of this novel histologic pattern to facilitate distinction between the two disorders.
Lichen sclerosus with histopathologic features simulating early mycosis fungoides.
Citarella L, Massone C, Kerl H, Cerroni L.
Department of Dermatology, University of Graz, Austria.
Am J Dermatopathol. 2003 Dec;25(6):463-5 Abstract quote.
Mycosis fungoides (MF) is a cutaneous T-cell lymphoma characterized in its early stages by a superficial band-like infiltrate with epidermotropism of lymphocytes without particularly atypical cytologic features. Even though clinicopathologic presentation is diagnostic in typical cases, some inflammatory skin disorders can simulate the histopathologic features of early MF.
In this study we present data on 9 patients affected by lichen sclerosus (LS) (M:F ratio 8:1; age range 7-75 years; mean age 31.3 years; median age 13 years), who presented with histopathologic features simulating early lesions of MF. The histopathologic picture was characterized in all cases by a dense, band-like infiltrate of lymphocytes within the superficial dermis, with exocytosis of lymphocytes within the lower part of the epidermis. The papillary dermis was expanded and showed focally coarse bundles of collagen simulating MF. The typical signs of LS were either absent or present only focally. Molecular analyses of the TCRgamma gene rearrangement performed with the polymerase chain reaction (PCR) technique revealed a polyclonal smear in eight cases, and a monoclonal band in one.
Our study shows that LS can present with histopathologic features simulating early MF. Especially in cases revealing a monoclonal population of T lymphocytes by PCR, the correct diagnosis may be overlooked without proper clinical information and clinicopathologic correlation. Lichen sclerosus should be added to the list of cutaneous T-cell pseudolymphomas.
LYMPHOMATOID DRUG ERUPTIONS
Lymphomatoid Drug Eruption Mimicking Digitate Dermatosis: Cross Reactivity Between Two Drugs That Suppress Angiotensin II Function.
Am J Dermatopathol. 2003 Aug;25(4):331-4 Abstract quote
A 75-year-old male presented with an eruption characteristic of digitate dermatosis. The eruption cleared completely after discontinuation of lisinopril (angiotensin converting enzyme inhibitor). Eighteen months later a similar eruption recurred after using valsartan (a competitive inhibitor of angiotensin II receptor). The eruption cleared after discontinuation of valsartan. Histologic findings in both eruptions were consistent with lymphomatoid drug eruption.
This case is interesting in that the eruption occurred after the intake of two structurally unrelated drugs that interfere with angiotensin II function. This observation may shed light on the mechanisms that may be operative in provoking the lymphomatoid drug eruption.
Drug-induced reversible lymphoid dyscrasia: a clonal lymphomatoid dermatitis of memory and activated T cells.
Magro CM, Crowson AN, Kovatich AJ, Burns F.
Department of Pathology, Division of Dermatopathology, Ohio State University, Columbus, USA.
Hum Pathol 2003 Feb;34(2):119-29 Abstract quote
Certain systemic conditions predispose patients to excessive lymphocyte responses to immune-perturbing drugs, which may progress to malignant lymphoma. Many pathologists and clinicians believe that differentiation of pseudolymphoma from cutaneous T cell lymphoma (CTCL) can be reliably made through phenotypic and molecular analysis.
We encountered 15 cases of atypical cutaneous T-cell lymphoid hyperplasia in the setting of drug therapy. We explored phenotypic anomalies using antibodies to CD2, 3, 4, 7, 8, 20, 30 and CD62 K and sought T-cell receptor gene rearrangements by a polymerase chain reaction methodology. The lymphoid infiltrates showed reproducible CD7 and/or CD62 K deletion in concert with T cell clonality and variable CD30 positivity-findings similar to those of CTCL-but the rashes resolved or improved substantially after drug modulation.
We hypothesize that the infiltrates represent an unrepressed expansion of CD7- and CD62 K-negative activated memory T lymphocytes in response to antigenic triggers. We propose the term "drug-induced reversible lymphoid dyscrasia" to describe this entity.
- J Am Acad Dermatol. 2006 Sep;55(3):467-77 Abstract quote
BACKGROUND: T-cell prolymphocytic leukemia (T-PLL), formerly categorized as T-cell chronic lymphocytic leukemia, is a rare and aggressive hematologic malignancy. Although the skin is characteristically involved, it is not a well-recognized entity in the dermatologic literature.
METHODS: Six cases of cutaneous T-PLL are presented from a clinical, light microscopic, and phenotypic perspective.
RESULTS: The patient population comprised 2 women and 4 men, with a mean age of 69.8 years. The disease was associated in all with skin involvement with facial preference; edema, purpura, and lesional symmetry were characteristic. The skin biopsies demonstrated a largely non-epidermotropic angiocentric lymphocytic infiltrate with accompanying hemorrhage. The cells showed irregular- to reniform-shaped nuclei with small nucleoli and eosinophilic rims of cytoplasm. Phenotypic studies revealed three prevailing profiles: CD4 dominant in 4, CD8 dominant in one, and co-expression of CD4 and CD8 in one. CD3 loss was seen in one case. All expressed T-cell leukemia 1 (TCL-1) and CD7; cutaneous lymphocyte antigen expression was discernible in a dot-like perinuclear array. All cases tested excluding one expressed TCL-1 and CD52. In two cases tested, T-cell receptor beta rearrangements were observed. Cytogenetic studies demonstrated a paracentromeric chromosome 14 inversion. Polysomy 8 and MYC amplification was seen in one case, manifesting an aggressive clinical course. Four patients died from their disease within 18 months of diagnosis.
LIMITATIONS: Cytogenetic MYC amplification, FISH, and TCR beta studies were conducted on each of 2 cases, respectively, due to limitations of tissue block samples and/or peripheral blood. cMYC translocation studies were conducted on 3 of the 6 cases, again due to limitations imposed by the tissue samples on the cases. The last case was recently diagnosed and, therefore, long-term follow-up is not possible.
CONCLUSION: T-PLL is a distinctive post-thymic T-cell malignancy with frequent cutaneous tropism. A diagnosis is possible in almost all cases based on characteristic clinical, light microscopic, phenotypic, and cytogenetic features. While a chromosome 14 inversion is highly characteristic, additional inherent cytogenetic differences, such as trisomy 8 with CMYC over-amplification, may account for some case to case variation in clinical course.
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Epidermotropism-Tendency for dermal lymphocytes to infiltrate into the overlying epidermis.
Gamma-Delta Cutaneous T-cell Lymphoma
Lutzner cell-Characteristic lymphocyte with convoluted or cerebriform nucleus. Sometimes known as Sezary cell.
Pautrier microabscess -Intraepidermal collections of atypical lymphocytes.
Woringer-Kolopp Disease (Pagetoid Reticulosis)
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