Cutaneous Malignant Lymphoma Research Articles

Phenotypic heterogeneity of mycosis fungoides cells leads to the difficulties in determining tumour origin.

Mycosis fungoides (MF) is a low-grade malignant cutaneous T-cell lymphoma that originates from memory T cells. It typically follows a unique and relatively indolent disease course. MF is used to be characterized by a tissue-resident memory T cell (TRM) phenotype, although recent molecular research has revealed its complexity, casting doubt on the cell of origin and the TRM-MF paradigm. Recent clonal heterogeneity studies suggest that MF may originate from immature early precursor T cells. During development, the tumour microenvironment (TME) influences tumour cell phenotype. The exact origin and development trajectory of MF remains elusive. Clarifying the origin of MF cells is vital for accurate diagnosis and effective treatment.

Cutaneous lymphoproliferative disorders: Back to the future.

In the 1980s, immunohistochemistry and clonality analyses became instrumental in the recognition and definition of new types of cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL) and the development of new classifications. By accepting loss of pan-T-cell antigens and clonal T-cell receptor gene rearrangements as important criteria to differentiate between benign and malignant T-cell proliferations, and monotypic immunoglobulin light-chain expression and clonal immunoglobulin gene rearrangements as crucial criteria to distinguish between benign and malignant B-cell proliferations, many cases, until then diagnosed as cutaneous lymphoid hyperplasia or pseudolymphoma, were reclassified as primary cutaneous CD4+ small/medium T-cell lymphoma (PCSM-TCL) or primary cutaneous marginal zone lymphoma (PCMZL), respectively. However, in recent years there is growing awareness that neither these immunohistochemical criteria nor demonstration of T-cell or B-cell clonality is specific for malignant lymphomas. In addition, many studies have reported that these low-grade malignant CTCL and CBCL have an indolent clinical behavior and an excellent prognosis with disease-specific survival rates of or close to 100%. As a result, recent classifications have downgraded several low-grade malignant cutaneous lymphomas to lymphoproliferative disorder (LPD). Both the 5th edition of the WHO classification (2022) and the 2022 International Consensus Classification (ICC) of mature lymphoid neoplasms reclassified PCSM-TCL as primary cutaneous CD4+ small/medium T-cell LPD and primary cutaneous acral CD8+ T-cell lymphoma as primary cutaneous acral CD8+ T cell LPD. While the 2022 ICC introduced the term "primary cutaneous marginal zone LPD," in the 5th edition of the WHO classification PCMZL is maintained. In this review we describe the background and rationale of the continually changing terminology of these conditions and discuss the clinical consequences of downgrading malignant lymphomas to LPDs.

Features of tattoo-associated cutaneous lymphoid hyperplasia on reflectance confocal microscopy and line-field confocal optical coherence tomography.

The popularity of tattoos has led to an increase in associated skin reactions, including complications such as infection, allergic reactions and rare conditions such as tattoo-induced cutaneous lymphoid hyperplasia (CLH). CLH is a benign lymphoproliferative reaction with clinical features resembling malignant cutaneous lymphomas. Non-invasive diagnostic tools like reflectance confocal microscopy (RCM) and the new line-field confocal optical coherence tomography (LC-OCT) are being studied in dermatology better to understand the morphological patterns of many dermatological diseases. Between September 2021 and May 2023, patients with suspicious lesions for tattoo-related CLH were analysed using RCM and LC-OCT before confirming the diagnosis of CLH through skin biopsy and histopathological examination. The study included five cases of CLH. It focused on the analysis of high-quality LC-OCT images/videos and RCM images to investigate the features of CLH in tattooed individuals. Most (80%) cases exhibited a mixed T and B lymphocyte infiltration subtype, while 20% showed a predominant T infiltration subtype. RCM and LC-OCT revealed characteristic features, including architectural disarray, fibrosis, lymphoid infiltrates, and pigment deposits in the epidermis and dermis. Non-invasive tools such as RCM and LC-OCT are valuable in diagnosing tattoo-related CLH. While skin biopsy remains the current standard for diagnosis, RCM and LC-OCT can serve as helpful adjuncts in identifying the most representative area for biopsy. They may potentially become alternative diagnostic options in the future, offering benefits in terms of cost, diagnostic efficiency, aesthetics and patient satisfaction as the prevalence of tattoo-related adverse reactions continues to rise.

DNA methylation alterations caused by Leishmania infection may generate a microenvironment prone to tumour development.

DNA methylation is an epigenetic signature consisting of a methyl group at the 5’ cytosine of CpG dinucleotides. Modifications in DNA methylation pattern have been detected in cancer and infectious diseases and may be associated with gene expression changes. In cancer development DNA methylation aberrations are early events whereas in infectious diseases these epigenetic changes may be due to host/pathogen interaction. In particular, in leishmaniasis, a parasitic disease caused by the protozoan Leishmania, DNA methylation alterations have been detected in macrophages upon infection with Leishmania donovani and in skin lesions from patients with cutaneous leishmaniasis. Interestingly, different types of cancers, such as cutaneous malignant lesions, lymphoma and hepatocellular carcinoma, have been diagnosed in patients with a history of leishmaniasis. In fact, it is known that there exists an association between cancer and infectious diseases. Leishmania infection may increase susceptibility to develop cancer, but the mechanisms involved are not entirely clear. Considering these aspects, in this review we discuss the hypothesis that DNA methylation alterations induced by Leishmania may trigger tumorigenesis in long term infection since these epigenetic modifications may enhance and accumulate during chronic leishmaniasis.

STING expression is an independent prognostic factor in patients with mycosis fungoides

Mycosis fungoides is recognized as an indolent cutaneous malignant T-cell lymphoma. In contrast, there are few therapeutic options for advanced forms of mycosis fungoides. Since immunotherapy is desirable as an alternative therapeutic option, identifying candidate molecules is an important goal for clinicians. Although tumor-derived negative immunomodulatory molecules, such as PD-1/PD-L1, have been identified in various malignancies, the useful positive immunological drivers of mycosis fungoides are largely unknown. We found that the stimulator of interferon (IFN) genes (STING) was highly upregulated in early-stage mycosis fungoides. Immunohistochemical examination revealed different STING staining patterns in patients with mycosis fungoides. Although there were no significant differences in clinical factors’ characteristics, STING expression was associated with the survival of patients with mycosis fungoides. The survival rate was significantly poor in patients with low STING-expressing mycosis fungoides. Univariate and multivariate analyses revealed that low STING expression was associated with an increased hazard ratio. Our results indicate that STING expression independently influences the prognosis of mycosis fungoides.

Dosimetry, Optimization and FMEA of Total Skin Electron Irradiation (TSEI)

PurposeTotal Skin Electron Irradiation (TSEI) is a method for treating malignant cutaneous T-cell lymphomas. This work aims to implement and optimize the total skin technique established at Strahlenklinik Erlangen, Germany on two new linear accelerators and to quantify the risks using failure mode and effects (FMEA) analysis. Material and methodsTSEI is performed at a VersaHD accelerator (Elekta, Stockholm) with 6MeV in the “high dose rate mode” HDRE and a nominal field size of 40×40cm2. To reach the entire skin surface, the patients perform 6 different body positions at a distance of 330cm behind an acrylic scatter plate, with two overlapping irradiation fields being radiated at 2 gantry angles per position. The irradiation technique was commissioned according to the recommendation of AAPM report 23. With the help of a reference profile at 270°, 2 gantry angles were calculated, which in total resulted in an optimal dose distribution. This was metrologically verified with ion-chamber measurements in the patient's longitudinal axis. The influence of the shape of the acrylic scatter plate and the distance between the acrylic scatter plate and patient was determined by measurements. The dose homogeneity was verified using an anthropomorphic disc phantom equipped with GafChromic films. The workflows and failure modes of the total skin technique were described in a process map and subsequently quantified with a FMEA analysis. ResultsAn optimal dose distribution is achieved at a distance of SSD=330cm, using the gantry angles 289° and 251°. The previously used segmented acrylic scatter plate was replaced by a flat plate (200×120×0.5cm3), which is placed at a distance of 50cm in front of the patient. The densitometric evaluation of the GafChromic films in the anthropomorphic disc phantom revealed an expected dose distribution of 3Gy at a depth of up to 1.5cm below the skin surface, with a homogeneity of ±10% over the phantom's longitudinal axis. By FMEA a maximum risk priority number of 30 was determined. ConclusionBased on the calculations and measurements performed on the new accelerators as well as the risk analysis, we concluded that total skin therapy can be implemented clinically.

PLCγ1/PKCθ Downstream Signaling Controls Cutaneous T-Cell Lymphoma Development and Progression

Developing mechanistic rationales can improve the clinical management of cutaneous T-cell lymphomas. There is considerable genetic and biological evidence of a malignant network of signaling mechanisms, highly influenced by deregulated TCR/PLCγ1 activity, controlling the biology of these lesions. In addition, activated signal transducer and activator of transcription 3 is associated with clinical progression, although the alterations responsible for this have not been fully elucidated. Here, we studied PLCγ1-dependent mechanisms that can mediate STAT3 activation and control tumor growth and progression. Downstream of PLCγ1, the pharmacological inhibition and genetic knockdown of protein kinase C theta (PKCθ) inhibited signal transducer and activator of transcription 3 activation, impaired proliferation, and promoted apoptosis in cutaneous T-cell lymphoma cells. A PKCθ-dependent transcriptome in mycosis fungoides/Sézary syndrome cells revealed potential effector genes controlling cytokine signaling, TP53, and actin cytoskeleton dynamics. Consistently, an invivo chicken embryo model xenografted with mycosis fungoides cells showed that PKCθ blockage abrogates tumor growth and spread to distant organs. Finally, the expression of a number of PKCθ target genes found in mycosis fungoides cells significantly correlated with that of PRKCQ (PKCθ) in 81 human mycosis fungoides samples. In summary, PKCθ can play a central role in the activation of malignant cutaneous T-cell lymphoma mechanisms via multiple routes, including, but not restricted to, STAT3. These mechanisms may, in turn, serve as targets for specific therapies.

Tre-O2-03 - Mogamulizumab-associated rash frequently mimics cutaneous T-cell lymphoma recurrence but heralds a positive response to therapy: an updated single-center case series

Mogamulizumab is a humanized antibody that targets CCR4, a transmembrane chemokine receptor predominantly expressed on effector T helper type 2 and malignant cutaneous T-cell lymphoma (CTCL) cells. This biologic was FDA approved for relapsed/refractory mycosis fungoides (MF)/Sézary syndrome (SS) in 2018. MARs are the most common adverse events reported; however, the clinicopathologic nature of these eruptions remains unclear. To inform future management and recognition of MAR, we report an update on our retrospective case series of MF/SS patients treated with mogamulizumab since its approval as standard of care. Among 24 CTCL (16 SS, 8 MF) patients, 17 developed MAR (68%). MAR development was associated with complete (11/17) or partial (4/17) responses, for an overall response rate (ORR) of 88% to mogamulizumab among patients with MAR. A lower ORR of 28% (2/7) was observed in patients that did not develop MAR. Median MAR time to onset (TTO) was 2.1 mo. (0.7–9.0). Median time to resolution (TTR) was 6.9 mo. (3.5–9.2) in 8/17 patients with MAR resolution. Five distinct but frequently concurrent clinical patterns were identified: lichenoid papules and plaques (9/17), MF-like lesions (9/17), photodistribution (7/17), psoriasiform plaques (7/17), and SS-like erythroderma (3/17). Histopathologic patterns included spongiotic (n=21), lichenoid (n=14), psoriasiform (n=10), and interface (n=8) features across 27 skin biopsies. Eosinophils (n=15), epithelioid granulomas (n=4), and bizarre bi- and multinucleated cells (n=6) that may represent highly activated macrophages were also noted. Although mild, features associated with CTCL were noted in all suspected MAR tissue samples [epidermotropism (n=10), exocytosis (n=12), and lymphoid atypia (n=16)]. When compared to baseline studies, flow cytometry analysis for circulating Sézary cells and TCR rearrangement studies in skin and blood were most often negative during suspected MAR despite the presence of CTCL-associated histological features, emphasizing the importance of ancillary studies in distinguishing MAR from CTCL. In conclusion, MAR may be characterized by distinct clinical, histopathologic, and molecular patterns. Notably, MAR can clinically mimic CTCL lesions and may occur more often in patients with clinical responses, highlighting the need for clinicians to rule out progressive disease vs. drug eruption in treating a condition that historically suffers from poor outcomes and treatment response.

Granuloma annulare - is it a paraneoplastic condition for malignant lymphoma?

In recent years, an association between granuloma annulare and the occurrence of malignant cutaneous lymphomas in the sense of a facultative paraneoplasia has been observed several times. The aim of the present work is to provide an overview of the currently available literature on granuloma annulare as well as an analysis of its association with cutaneous lymphomas. Using the example of two patients with granuloma annulare and associated cutaneous lymphomas, we would like to sensitize clinically active dermatologists and dermatopathologists to the possible association between these two diseases. Characteristic features and clinicopathological signs are discussed, which should raise suspicion of an associated malignant lymphoma. It is recommended to rule out an underlying cutaneous and/or extracutaneous lymphoma in unusual clinical constellations (for instance distribution pattern, subjective complaints, age at first manifestation, lack of response to conventional therapy), especially in the absence of other known clinical triggers of granuloma annulare such as insect bites, trauma or varicella-zoster infections, among others. However, in individual cases the criteria mentioned here justify lymphoma screening.

Research Progression of Subcutaneous Panniculitis-like T-Cell Lymphoma--Review

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a very rare cutaneous malignant lymphoma derived from cytotoxic T cells that mainly involves subcutaneous adipose tissue rather than epidermis and dermis. It usually occurs in young and middle-aged population, and the etiology is currently unclear. Clinically, SPTCL is characterized by subcutaneous plaques, nodules, and skin ulcers with swell and ache, mainly presenting in limbs and trunk. SPTCL has been restricted to cases that express α/β phenotype, whereas cases with γ/δ phenotype are categorized to cutaneous γ/δ+ T cell lymphoma by WHO-EORTC classification. The standard treatment for SPTCL is not definite with a relatively good prognosis. The recent research progression of SPTCL is summarized in this review.

Mycosis fungoides and gastric T-cell lymphoma: A case report.

Mycosis fungoides (MF) is a cutaneous malignant lymphoma with an extended clinical course. MF presents in series of dermatological manifestations, beginning with patches and plaques of the skin, and eventually evolving into tumours. Often MF can occur for extended periods without worsening of external symptoms, while the disease advances internally in organs such as lymph nodes, liver, spleen, lung, bone marrow, gastrointestinal tract, pancreas and kidney. The present report presents a clinical case in which gastrointestinal symptomatology occurred a decade after the first dermatological manifestation. Immunohistochemical analysis of the skin, along with small bowel biopsies revealed evidence of gastric T-cell lymphoma. To the best of our knowledge, the present study is the first to describe such a case in the literature.

18F-FDG PET/CT in Lymphomatoid Papulosis Mimicking Primary Cutaneous Anaplastic Large Cell Lymphoma

Lymphomatoid papulosis is a benign self-healing condition, presenting as papulonodular skin eruptions and mimicking malignant cutaneous lymphomas histopathologically. F-FDG PET/CT findings in this benign condition have not been described in detail in the literature. We present a case of lymphomatoid papulosis mimicking primary cutaneous anaplastic large cell lymphoma histopathologically and demonstrating intensely FDG-avid cutaneous lesions on F-FDG PET/CT, which disappear spontaneously in the follow-up scan.

Cutaneous Pseudolymphoma: A Brief Review and Report of a Case Treatment Using Rituximab

Cutaneous pseudolymphoma (C-PSL) is characterized by heterogenous lymphoproliferative processes contributing to skin lesions which histologically and clinically mimic malignant cutaneous lymphomas. It is of most importance to diagnose such case precisely and discriminate them from malignant lymphomas since treatment protocols are distinctive. Standard medical approaches for C-PSL includes elimination of causative factors, topical, intralesional and systemic steroids, hydroxychloroquine, and photodynamic therapy. Rituximab as an anti CD20 monoclonal antibody was used in this study to treat a patient with 8 years clinical features of pseudolymphoma with no positive response to routine medications. Follow up of almost more than 18 months revealed a successful treatment without noticeable side effects or disease recurrence.

Tumeur évoluée du tronc d’origine lymphomateuse

Malignant lymphomas are a group of cancers that arise in the lymphoid tissue, in the lymph nodes or in extranodal sites due to neoplastic lymphocytic cell transformation. Within this group, malignant non-Hodgkin lymphomas are distinctive. We report a case of diffuse advanced and extremely aggressive malignant cutaneous non-Hodgkin lymphoma. The study involved a 30-year old patient, driver, married and father of one child, followed-up in the Department of Hematology and Oncology for 2 years due to malignant non-Hodgkin lymphoma diagnosed on the basis of axillary and inguinal polyadenopathies. The patient underwent 13 chemotherapy sessions. He was admitted to the Department of Plastic, Cosmetic and Burn Surgery at the University Hospital Mohammed VI in Marrakech with skin involvement of his lymphoma manifesting as an advanced left latero-thoracic tumor rapidly increasing in size. On clinical examination, his general condition was quite good. It showed voluminous left latero-thoracic mass adherent to its deeper structure with ipsilateral axillary shield. Partial biopsy was performed. Anatomo-pathological examination confirmed the diagnosis of diffuse malignant large B-cells non-Hodgkin's lymphoma. Immunohistochemical and genetic study was not performed. Serology tests were negative. Serial Computed Tomography (CT) scan showed voluminous left antero-lateral predominantly axillary and thoracic ganglionic mass made of confluent lymph nodes, with persistence of peripheral lymph nodes, skin ulcers and necrotic areas measuring 30cm in diameter. In our Hospital, the patient underwent wide tumor resection, then coverage with a split-thickness skin, thus reducing tumor volume and ensuring better patient's comfort. When the patient started healing, he was referred to the Department of Hematology and Oncology for complementary treatment.

Preliminary discussion on the value of 18F-FDG PET/CT in the diagnosis and early staging of non-mycosis fungoides/Sézary's syndrome cutaneous malignant lymphomas

ObjectiveTo discuss the value of 18F-fluorodeoxyglucose-positron emission tomography (18F-PET/CT) scans in the diagnosis and early staging of non-mycosis fungoides/Sézary's syndrome cutaneous malignant lymphomas (non-MF/SS CML). Materials and methodsA total of 18 cases with non-MF/SS CML, confirmed by pathology or on clinical grounds, were analyzed in this study. The sensitivity of CT and PET/CT scans in the diagnosis of primary skin lesions, as well as the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of CT and PET/CT scans in the diagnosis of lymph nodes (LNs) and other organs (except skin and LNs) were calculated. ResultsThe diagnostic sensitivity of CT and PET/CT scans in the diagnosis of primary skin lesions was 82.4% (14/17) and 100% (17/17), respectively. The diagnostic sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of CT and PET/CT scans in the diagnosis of LN lesions were 55.6% (5/9), 88.9% (8/9), 72.2% (13/18), 83.3% (5/6), 66.7% (8/12), and 88.9% (8/9), 100% (9/9), 94.4% (17/18), 100% (8/8), 90.0% (9/10), respectively. The diagnostic value of the CT and PET/CT scans in the diagnosis of involvement of other organs, were 40.4% (2/5), 100% (13/13), 83.3 (15/18), 100% (2/2), 81.3% (13/16) and 80.6% (4/5), 100% (13/13), 94.4% (17/18), 100% (3/3), 92.9% (13/14), respectively. Conclusions18F-FDG PET/CT has high value in the diagnosis and early staging of non-MF/SS CMLs.

A Rare Kind of Lymphoma in a Patient on Treatment With Two Different Biological Agents

©2015 Turkish League Against Rheumatism. All rights reserved. Cutaneous pseudolymphoma (CPL) is a term used to indicate a group of skin disorders defined as benign lymphoprolipherative reactions that may simulate cutaneous malignant lymphomas clinically and/or histologically.1 These lesions represent a response to trauma, insect bites, stings, infections, tattoos, vaccinations, injection of foreign substances, pierced body jewelry, various drugs, and other undetermined stimuli.2-7 Not many papers are published regarding this disease since it is not commonly found in everyday clinical practice. It is essential to diagnose CPL as early as possible and differentiate it from skin Bor T-cell lymphoma.

A Case of Mycosis Fungoides in the Larynx and Pharynx

Mycosis fungoides (MF) is the most common type of cutaneous malignant T-cell lymphoma, but reports of MF in the head and neck region are rare. We report herein on a case we experienced in which MF invaded the larynx and pharynx. An 80-year-old man, who was seeing his dermatologist, visited a local hospital complaining of dysphagia, where a lesion in the epiglottis on the right aryepiglottic folds was discovered, and the patient was referred to our hospital for further examination. A biopsy of the area of interest confirmed the presence of MF and the patient was immediately sent for radiation therapy. Three months thereafter, an elevated MF lesion appeared on the posterior part of the tongue, so the patient underwent additional radiation therapy of the entire pharynx. Since no recurrence was seen 12 months after the end of the treatment regimen in our department, radiotherapy for potentially malignant lesions of the larynx and pharynx is suggested as a valid approach.

Cutaneous malignant lymphomas

Cutaneous malignant lymphomas

The role of molecular and genetic methods to determine theТ-cell and В-cell clonality in diagnosing malignant cutaneouslymphomas

The article presents the data on the studies contributing to improving the differential diagnostics of T-cell and B-cell cutaneous lymphomas including large-plaque parapsoriasis and T-cell and B-cell cutaneous pseudolymphomas as well as frequency of their transformation into malignant cutaneous lymphomas. There was a study of 101 patients using the polymerase chain reaction method to determine the T-cell and B-cell lymphocyte clonality by genes of g and ƒ chains in the T-cell receptor and immunoglobulin heavy chain genes. Monoclonality was determined in 40 of 46 cases in patients with T-cell cutaneous lymphomas and in three of four cases in patients with B-cell cutaneous lymphomas. Monoclonality was revealed in one of 14 cases of large-plaque parapsoriasis and one of two cases of T-cell cutaneous pseudolymphoma. In all of the 24 cases of chronic benign dermatoses, five cases of small-plaque parapsoriasis and ten skin tissue samples obtained from healthy donors, polyclonal lymphocytes were revealed. So, the obtained results make it possible to consider the method to be an important addition in the field of diagnosing lymphoproliferative skin diseases.

Le lymphocytome borrélien du lobe de l’oreille

We describe a 6-year-old boy who developed Borrelia burgdorferi-associated lymphocytoma cutis on the ear. Lymphocytoma is a benign polyclonal B-cell lymphoproliferative process; it is defined as a subacute manifestation of early disseminated borrelial infection. Clinical history, physical examination, and serodiagnosis tests are often sufficient to establish diagnosis, but sometimes, histopathologic analysis is needed to exclude malignant cutaneous lymphomas. The outcome is always favorable but after antibiotic therapy, the lesion disappears promptly.