Mycosis fungoides (MF) stands as the predominant form of primary cutaneous T-cell lymphoma (CTCL). It manifests a diverse array of clinical, histological, and immunophenotypic variations, each bearing distinct prognostic implications. The typical immunophenotypic profile of mycosis fungoides involves CD3+/CD4+/CD45RO+ memory T cells. Notably, the CD4-/CD8- double-negative variant of MF is a rare occurrence, observed in approximately 12% of early-stage cases and more prevalent in tumor-stage instances, often correlated with atypical clinical presentations. Despite its rarity, scant information is available about double-negative mycosis fungoides, with only a limited number of cases documented in the existing literature. This review aims to provide enhanced clarity, comprehension, and a detailed exploration of the spectrum encompassing double-negative mycosis fungoides.

Mycosis fungoides (MF) represents the most common type of primary cutaneous T-cell lymphoma. Recognition of MF variants with divergent immunophenotypes is important for accurate diagnosis and appropriate management, as they can be confused with other lymphoma subtypes. We present a case of a 49-year-old male previously diagnosed with a cutaneous lymphoproliferative disorder with an unusual NK/T-cell phenotype. He presented with a 10-year history of pelvic girdle rash involving the right hip and upper thigh. The lesions were characterized as atrophic patches concentrated in sun-protected areas and involving 10% of the body surface area. Shave biopsies revealed an atypical epidermotropic infiltrate composed of hyperchromatic small to medium-sized lymphocytes with perinuclear halos and "tagging" along the dermal-epidermal junction. The immunophenotype was unusual in that the neoplastic lymphocytes showed complete loss of pan T-cell antigens along with expression of CD56, cytotoxic markers, and weak CD20. All other B-cell markers were negative. The combination of clinical findings, in addition to the histopathologic and immunophenotypic profile, were diagnostic of null T-cell phenotype MF with aberrant expression of CD56 and CD20. Null T-cell phenotype MF is very uncommon, can be diagnostically challenging, and can mislead the diagnosis of aggressive lymphoma subtypes.

Comprehensive data on childhood mycosis fungoides (MF) is scarce.

To describe clinical features, immunophenotypes, various treatment options, and prognosis of MF in children and adolescents.

This systematic review searched MEDLINE via PubMed, Embase, Cochrane, and Scopus databases in October 2019. The search terms included mycosis fungoides, infant, children, and adolescent. No filter for the publication period was used, but studies written in a language other than English were excluded. Reference lists of the relevant articles were also searched manually. Case series and case reports were included if data on childhood MF were extractable. The Asan Medical Center database for cases of childhood MF was also searched. Patients were treated from January 1, 1990, to July 31, 2019, and were younger than 20 years at the time of diagnosis. The methodologic quality of the included studies was assessed with items from the Newcastle-Ottawa scale. Data were analyzed from December 9, 2019, to September 4, 2020.

A total of 571 unique patients were included. The mean (SD) age at diagnosis was 12.2 (4.2) years; at onset, 8.6 (4.2) years. The female-to-male ratio was 1:1.6 (350 male patients [61.3%]). Among 522 patients with data available at diagnosis, stage 1 disease constituted 478 cases (91.6%), followed by stage 2 (39 [7.5%]) and stage 4 (5 [1.0%]). Among the 567 patients with data available, the most common variant of MF was the hypopigmented form (309 [54.5%]), followed by classic MF (187 [33.0%]). The MF lesions were predominantly the CD4+ and CD8+ immunophenotype in 99 (49.5%) and 79 (39.5%) of 200 patients, respectively. Among the treatments, narrowband UV-B was the most frequently used (150 of 426 [35.2%]). Most patients were alive with the disease (185 of 279 [66.3%]); 83 of 279 (29.8%) were in complete remission; and 11 of 279 (3.9%) had died by the last follow-up. A longer time from onset to diagnosis (hazard ratio [HR], 1.24; 95% CI, 1.06-1.45), granulomatous slack skin (HR, 12.25; 95% CI, 1.99-75.26), granulomatous MF (HR, 14.59; 95% CI, 1.31-162.00), a history of organ transplant (HR, 10.15; 95% CI, 0.98-105.37), and stage 2 disease at the time of diagnosis (HR, 10.22; 95% CI, 2.94-35.50) were associated with worse outcomes.

The findings of this review suggest that there is often a significant delay until the establishment of a correct diagnosis of childhood MF, which may be detrimental to the prognosis.

Hypopigmented mycosis fungoides (HMF) is a form of cutaneous T-cell lymphoma (CTCL), a heterogeneous group of extranodal non-Hodgkin's lymphomas. HMF has a unique set of defining features that include light colored to achromic lesions, a predilection for darker skin phototypes, an early onset of disease, and predominance of CD8⁺ T-cells, among others. In the current review, we detail the known pathways of molecular pathogenesis for this lymphoma and posit that an active Th1/cytotoxic antitumor immune response in part explains why this variant is primarily seen in children/adolescents and young adults, who do not exhibit signs of immunosenescence. As a result of this potent cytotoxic response, HMF patients experience mostly favorable overall prognosis, while hypopigmentation may in fact represent a useful surrogate marker of cytotoxic immunity targeting the malignant cells. Understanding the molecular processes behind the specific features that define HMF may lead to improved diagnostic accuracy, personalized prognosis by risk stratification, and improved management of HMF. Moreover, improving our knowledge of HMF may aid our further understanding of other cutaneous lymphomas.

Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare but aggressive cancer characterised by angiocentric and angiodestructive infiltration by NK-cells, or cytotoxic T-cell types. Histopathologically, ENKTL shows a multinodular or diffuse infiltration localised to vascular structures, resulting in angiodestruction and necrosis. We present a patient with an initially suspected diagnosis of benign interface dermatitis with a differential diagnosis of mycosis fungoides that was later found to be an aggressive extranodal natural killer/T-cell lymphoma of a nasal type and with a dismal prognosis.

Less than 5% of cases of mycosis fungoides (MF) present with a cytotoxic/suppressor CD8⁺ phenotype. This study aimed to evaluate the clinical characteristics, treatment modalities, and clinical course in CD8⁺ MF patients.

In a retrospective analysis of 353 MF patients in a referral center at Ankara University, Turkey, 29 patients that were diagnosed with CD8⁺ MF were included in the study.

CD8⁺ MF cases constituted 8.2% of all MF patients. The age at the time of diagnosis ranged between 6 and 81 years with a median value of 46 years. The female-to-male ratio was 1.41. Patients presented with erythematous scaly (69%), hyperpigmented (58.6%), poikilodermic (17.2%), and hypopigmented (17.2 %) patches/plaques. The most common sites of involvement were the trunk and lower extremities. The most common comorbidity was hypertension (24.1%, n: 7) with 13 patients (44.8%) having a history of at least one autoimmune disease. At the time of diagnosis, 93.2% of the patients had early-stage disease, and 6.8% of the patients had advanced stage. The mean follow-up period was 6.68 ± 6.04 years (range 1-28 years). Most of the patients were treated with skin-directed therapies. Complete remission was achieved in 17 (58.6%) patients, eight (27.6%) patients had partial remission, and four (13.8%) patients had stable disease.

We concluded that CD8⁺ MF is associated with an indolent course and in most patients, skin-directed therapies were found to be efficient to control the disease.

Mycosis fungoides, the most common subtype of cutaneous T-cell lymphoma, displays a broad spectrum of clinical, histological and phenotypic variants with different prognostic impacts. The classic immunophenotype is CD3+/CD4+/CD45RO+memory T cells. CD4/CD8 double-negative mycosis fungoides is rare. Here we describe the clinicopathological features of CD4/CD8 double-negative mycosis fungoides in a 55-year-old female with a review of the literature. Although the CD4/CD8 double-negative phenotype appears to be associated with an unusual clinical presentation, it does not appear to confer prognostic significance.

This article focuses on cutaneous hematopoietic neoplasms that are more likely to be encountered in the pediatric age-group and includes both lymphoproliferative and histiocytic disorders. The cutaneous hematologic disorders in children have a different epidemiologic profile to what is seen during adulthood. Although mycosis fungoides is the most frequent form of cutaneous lymphoma in adults, it is very rare in children. Because lymphoblastic leukemias and lymphomas are more frequent in the pediatric setting, cutaneous leukemic infiltrates are relatively common in this age-group. Similarly, histiocytic disorders are more common in children, particularly Langerhans cell histiocytosis and juvenile xanthogranuloma. Notably, the histiocytic disorders have undergone significant modifications on their nomenclature in the basis of the molecular characteristics that are present in them. A summary of the most frequent cutaneous hematopoietic disorders in children will be discussed further in this review.

Aggressive epidermotropic cutaneous CD8(+) lymphoma is currently afforded provisional status in the WHO classification of lymphomas. An EORTC Workshop was convened to describe in detail the features of this putative neoplasm and evaluate its nosological status with respect to other cutaneous CD8(+) lymphomas.

Sixty-one CD8(+) cases were analysed at the workshop; clinical details, often with photographs, histological sections, immunohistochemical results, treatment and patient outcome were discussed and recorded. Eighteen cases had distinct features and conformed to the diagnosis of aggressive epidermotropic cutaneous CD8(+) lymphoma. The patients typically present with widespread plaques and tumours, often ulcerated and haemorrhagic, and histologically have striking pagetoid epidermotrophism. A CD8(+) /CD45RA(+) /CD45RO(-) /CD2(-) /CD5(-) /CD56(-) phenotype, with one or more cytotoxic markers, was found in seven of 18 patients, with a very similar phenotype in the remainder. The tumours seldom involve lymph nodes, but mucosal and central nervous system involvement are not uncommon. The prognosis is poor, with a median survival of 12 months. Examples of CD8(+) mycosis fungoides, lymphomatoid papulosis and Woringer-Kolopp disease presented the typical features well documented in the CD4(+) forms of those diseases.

Aggressive epidermotropic cutaneous CD8(+) lymphoma is a distinct lymphoma that warrants inclusion as a distinct entity in future revisions of lymphoma classifications.

We report a 51-year-old woman with cutaneous involvement by extranodal NK/T-cell lymphoma (TCL) of the colon that microscopically mimicked mycosis fungoides (MF). She had a history of fever of unknown origin for 2 months and then developed multiple erythematous papules on her trunk and extremities. A skin biopsy revealed superficial infiltration by atypical small to medium-sized lymphocytes with epidermotropism and Pautrier collections. Immunohistochemical studies showed expression of CD3 and TIA-1 with lack of expression (double negative) of CD4 and CD8. Initially, we reported the diagnosis as MF, cytotoxic variant. Thereafter, computerized tomography scan incidentally identified a colonic mass. A colonic biopsy revealed infiltration of atypical lymphoid cells with the same morphology and immunophenotype as those found in the skin. Additionally, CD56 and Epstein-Barr virus-encoded RNA in situ hybridization in both skin and colonic biopsies were diffusely positive. Thus, extranodal NK/TCL was diagnosed. Delta T-cell receptor (TCR) gene rearrangement was documented in the skin biopsy by polyacrylamide gel electrophoresis and fluorescence capillary gel electrophoresis methods. There was no TCR gene rearrangement detected in the colonic biopsy. Unfortunately, the patient died within 2 months of diagnosis.

Cutaneous lymphoid infiltrates may pose some of the most difficult diagnostic problems in dermatopathology. Immunocytochemistry is often employed in an effort to determine whether an infiltrate is neoplastic or, in the case of clearly malignant infiltrates, to provide a specific diagnosis. The rarity of these disorders and the variant immunocytochemical profiles they may present further thwart understanding and sometimes prevent an accurate diagnosis. In this review the common immunocytochemical profiles of various cutaneous lymphomas are presented and potential pitfalls and problems considered. Immunocytochemistry is not a diagnostic test but, as in other areas of histopathology, is a highly valuable tool that requires critical interpretation within a context: so applied, it is an indispensable part of the pathologist's arsenal in evaluating lymphoid infiltrates and defining different lymphomas.

The major differential diagnosis for a primary cutaneous T-cell lymphoproliferative disorder with CD30 (Ki-1) positivity includes primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, pagetoid reticulosis and transformed mycosis fungoides (MF). Little is known, however, about CD30 expression in nontransformed MF, whether it simply reflects the proliferative fraction and if either CD30 staining or the proliferative fraction are of prognostic significance. Therefore, 47 nontransformed MF biopsies were stained for CD30 and Ki-67. The proportions of positive cells were determined and correlated with each other as well as with age, stage at diagnosis, maximum stage and survival. All cases had at least rare dermal CD30-positive cells. Higher percentages of dermal CD30 and Ki-67-positive cells were associated with a higher stage at diagnosis, and together with epidermal CD30, associated with a higher maximum stage. The proportion of CD30 and Ki-67-positive cells did not correlate with each other. Survivals were shorter if the dermal CD30 or epidermal or dermal Ki-67% were greater than the median (4.7%, 14%, 13%) and in patients of greater than or equal to 60 years of age or with a high stage. Dermal Ki-67 as a continuous variable was an independent prognostic indicator (P<0.001), as were dermal Ki-67 (P=0.004) and dermal CD30 (P=0.027) when analyzed as dichotomous variables but not stage. Therefore, CD30 expression is not restricted to transformed MF but higher levels of dermal CD30 expression and, even more so, dermal Ki-67 levels are independent adverse prognostic indicators.

Fewer than 5% of cases of mycosis fungoides (MF) present with a cytotoxic/suppressor CD8+ phenotype which, despite immunophenotypic similarities with CD8+ aggressive lymphomas, is regarded as a phenotypic variant of MF. Poikilodermatous MF showing a CD8+ phenotype has been reported to have a nonaggressive clinical behaviour and a good response to psoralen plus ultraviolet A treatment.

To perform a retrospective study of CD8+ MF cases diagnosed in the skin lymphoma clinic of Andreas Sygros Hospital.

We analysed the clinical characteristics, the immunophenotypic and molecular indices, as well as the clinical course of these patients.

Seven cases of CD8+ MF (6.5% of all cases of cutaneous T-cell lymphoma) were diagnosed during 2002-2007. One of seven patients had stage IA, five stage IB and one stage IIB disease. Clinical characteristics were variable: four of seven patients presented with poikilodermatous plaques (in one of them lesions of lymphomatoid papulosis with CD8+ phenotype coexisted), one patient with classic MF, one with plantar MF and one with follicular MF. The time period between disease onset and diagnosis was long for most patients (up to 33 years). All patients received the recommended treatment according to TNM staging. Five of seven patients had complete remission, one partial response and one stable disease.

Special clinical characteristics, such as hyperpigmentation and poikiloderma, are often noted in CD8+ MF cases. In our series CD8+ MF presented with a long-standing disease and indolent course suggesting that CD8+ cytotoxic immunophenotype may represent a marker of mild biological behaviour.

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.

Routine clinicopathologic practice is expected to refine/validate the scoring system proposed in 2005 by the International Society for Cutaneous Lymphomas (ISCL) for the diagnosing early mycosis fungoides (eMF), classical type.

An evaluation of 72 cases of erythematous and scaling dermatoses was employed with a partial implementation of the ISCL algorithm.

The selected cases fulfilled the clinical criteria proposed by the ISCL; routine histopathology allowed to reach the ISCL minimum score for a diagnosis of eMF in 45 cases. A clonal T-cell population was found in 4 out of 12 cases tested with the polymerase chain reaction, three of which with an already established clinicopathologic diagnosis of eMF. An aberrant immunophenotype was found in 11 cases, all of which already labeled as eMF on the basis of clinical and histopathologic features. 6 out of 27 patients with inconclusive clinicopathologic data underwent a new skin biopsy, which allowed to reach a diagnosis of eMF in two cases.

The diagnosis of eMF still rests upon clinical features and conventional histology; a new skin biopsy is recommended for cases with no clear-cut diagnostic features.

Mycosis fungoides (MF), a low-grade lymphoproliferative disorder, is the most common type of cutaneous T-cell lymphoma. Typically, neoplastic T cells localize to the skin and produce patches, plaques, tumours or erythroderma. Diagnosis of MF can be difficult due to highly variable presentations and the sometimes nonspecific nature of histological findings. Molecular biology has improved the diagnostic accuracy. Nevertheless, clinical experience is of substantial importance as MF can resemble a wide variety of skin diseases. We performed a literature review and found that MF can mimic >50 different clinical entities. We present a structured framework of clinical variations of classical, unusual and distinct forms of MF. Distinct subforms such as ichthyotic MF, adnexotropic (including syringotropic and folliculotropic) MF, MF with follicular mucinosis, granulomatous MF with granulomatous slack skin and papuloerythroderma of Ofuji are delineated in more detail.

We report 3 cases of lymphomatoid papulosis (LyP) with a CD56+, cytotoxic immunophenotype. All 3 patients presented with clinical histories typical of LyP, with one patient having associated mycosis fungoides. Histologically, two cases were type A LyP and one was type B. All 3 cases demonstrated a T-cell receptor clone in lesional skin without evidence of blood involvement. The atypical lymphocytes in each of the 3 cases expressed cytotoxic granules (T-cell intracellular antigen-1+ and granzyme B+) and were CD8+ and CD56+. Expression of CD56 is associated with a poor prognosis in subcutaneous panniculitis-like T-cell lymphoma and blastic natural killer cell lymphoma. However, the two cases of CD56+ LyP previously reported and the 3 cases in this series all appear to be pursuing an indolent course with no evidence of systemic disease.

Diagnosis and differential diagnosis of cutaneous lymphoproliferative disorders is one of the most difficult areas in dermatopathology, and biopsies are often taken to rule out a cutaneous lymphoma in patients with "unclear" or "therapy-resistant" skin lesions. Histopathological features alone often enable a given case to be classified to a diagnostic group (eg, epidermotropic lymphomas), but seldom allow a definitive diagnosis to be made. Performing several biopsies from morphologically different lesions is suggested, especially in patients with suspicion of mycosis fungoides. Immunohistochemistry is often crucial for proper classification of the cases, but in some instances is not helpful (eg, early lesions of mycosis fungoides). Although molecular techniques provide new, powerful tools for diagnosing cutaneous lymphoproliferative disorders, results of molecular methods should always be interpreted with the clinicopathological features, keeping in mind the possibility of false positivity and false negativity. In many cases, a definitive diagnosis can be made only on careful correlation of the clinical with the histopathological, immunophenotypical and molecular features.

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.

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.

Our departmental archives were searched for patients with early-stage MF and CD4/CD8 DN immunophenotpye.

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.

This was a single-center case series.

There is a subgroup of patients with early 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.

The new WHO/EORTC classification for cutaneous lymphomas comprises mature T-cell and natural killer (NK)-cell neoplasms, mature B-cell neoplasms, and immature hematopoietic malignancies. It reflects the unique features of lymphoproliferative diseases of the skin, and at the same time it is as compatible as possible with the concepts underlying the WHO classification for nodal lymphomas and the EORTC classification of cutaneous lymphomas. This article reviews the histological, phenotypical, and molecular genetic features of the various nosological entities included in this new classification. These findings always have to be interpreted in the context of the clinical features and biologic behavior.

To review the histological, phenotypical and molecular genetic features of the various nosological entities of the new WHO/EORTC classification for cutaneous lymphomas.

Extensive review of the literature cited in Medline and own data of the authors.

The WHO/EORTC classification of cutaneous lymphomas comprises mature T-cell and NK-cell neoplasms, mature B-cell neoplasms and immature hematopoietic malignancies. It reflects the unique features of primary cutaneous lymphoproliferative diseases.

This classification is as much as possible compatible with the concept of the WHO classification for nodal lymphomas and the EORTC classification of cutaneous lymphomas. The histological, phenotypical and molecular genetic features always have to be interpreted in the context of the clinical features and biologic behavior.