Clinical and Pathological Characteristics and Outcomes Among Patients With Subcutaneous Panniculitis-like T-Cell Lymphoma and Related Adipotropic Lymphoproliferative Disorders.

Importance: There is a knowledge gap about subcutaneous panniculitis-like T-cell lymphoma (SPTCL) owing to its rarity and diagnostic difficulty, resulting in an absence of well-documented large case series published to date. Objective: To generate consensus knowledge by a joint multi-institutional review of SPTCL and related conditions. Design, Setting, and Participants: This retrospective clinical and pathological review included cases initially diagnosed as SPTCL at 6 large US academic centers. All cases were reviewed by a group of pathologists, dermatologists, and oncologists with expertise in cutaneous lymphomas. Through a process of group consensus applying defined clinical and pathological diagnostic criteria, the cohort was classified as (1) SPTCL or (2) adipotropic lymphoproliferative disorder (ALPD) for similar cases with incomplete histopathological criteria for SPTCL designation. Exposures: Cases of SPTCL diagnosed between 1998 and 2018. Main Outcomes and Measures: The main outcome was disease presentation and evolution, including response to therapy, disease progression, and development of hemophagocytic lymphohistiocytosis. Results: The cohort of 95 patients (median [range] age, 38 [2-81] years; female-to-male ratio, 2.7) included 75 cases of SPTCL and 20 cases of ALPD. The clinical presentation was similar for both groups with multiple (61 of 72 [85%]) or single (11 of 72 [15%]) tender nodules mostly involving extremities, occasionally resulting in lipoatrophy. Hemophagocytic lymphohistiocytosis (HLH) was only observed in SPTCL cases. With a mean follow-up of 56 months, 60 of 90 patients (67%) achieved complete remission with a median (range) of 3 (1-7) cumulative therapies. Relapse was common. None of the patients died of disease progression or HLH. Two patients with ALPD eventually progressed to SPTCL without associated systemic symptoms or HLH. Conclusions and Relevance: In this case series of patients initially diagnosed as having SPTCL, results showed no evidence of systemic tumoral progression beyond the adipose tissue. The SPTCL experience in this study confirmed an indolent course and favorable response to a variety of treatments ranging from immune modulation to chemotherapy followed by hematopoietic stem cell transplantation. Morbidity was primarily associated with HLH.

Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity.

Cutaneous T-cell lymphomas (CTCLs) are a clinically heterogeneous collection of lymphomas of the skin-homing T cell. To identify molecular drivers of disease phenotypes, we assembled representative samples of CTCLs from patients with diverse disease subtypes and stages. Via DNA/RNA-sequencing, immunophenotyping, and ex vivo functional assays, we identified the landscape of putative driver genes, elucidated genetic relationships between CTCLs across disease stages, and inferred molecular subtypes in patients with stage-matched leukemic disease. Collectively, our analysis identified 86 putative driver genes, including 19 genes not previously implicated in this disease. Two mutations have never been described in any cancer. Functionally, multiple mutations augment T-cell receptor-dependent proliferation, highlighting the importance of this pathway in lymphomagenesis. To identify putative genetic causes of disease heterogeneity, we examined the distribution of driver genes across clinical cohorts. There are broad similarities across disease stages. Many driver genes are shared by mycosis fungoides (MF) and Sezary syndrome (SS). However, there are significantly more structural variants in leukemic disease, leading to highly recurrent deletions of putative tumor suppressors that are uncommon in early-stage skin-centered MF. For example, TP53 is deleted in 7% and 87% of MF and SS, respectively. In both human and mouse samples, PD1 mutations drive aggressive behavior. PD1 wild-type lymphomas show features of T-cell exhaustion. PD1 deletions are sufficient to reverse the exhaustion phenotype, promote a FOXM1-driven transcriptional signature, and predict significantly worse survival. Collectively, our findings clarify CTCL genetics and provide novel insights into pathways that drive diverse disease phenotypes.

High incidence of adnexotropism in cytotoxic cutaneous lymphomas.

BACKGROUND: Primary cutaneous gamma-delta T-cell lymphoma (PCγδTCL) and primary cutaneous aggressive epidermotropic T-cell lymphomas (PCAETCL) are rare aggressive cytotoxic cutaneous lymphomas (CyCL) often difficult to diagnose. Histopathologically, PCAETCL and PCγδTCL may resemble mycosis fungoides (MF) and the presence of adnexotropism in CyCL (CyCL) contributes to this diagnostic challenge, especially in the setting of atypical and double-negative phenotypes. METHODS: In this retrospective study clinical data and histopathological section of 91 patients were analyzed for signs of clinical and histopathological signs adnexotropism. RESULTS: Adnexotropism was identified in 48.4% (44/91) of cases, including PCAETCL (40.9%, 18/44), PCγδTCL and cytotoxic cutaneous lymphomas, not otherwise specified (CyCTCL, NOS) (43.2%, 19/44 and 15.9%, 7/44). Comparison between disease-related mortality with Kaplan-Meier survival analysis of non-adnexotropic vs adnexotropic CyCL did not show any significant difference between the two groups (P = 0.8). Clinically they present with patches, plaques, and tumors and commonly with ulceration, but follicular prominence or alopecia are rare. Clinical signs of adnexotropism such as alopecia and hypo- or anhidrosis were rarely seen. CONCLUSION: Adnexotropism is a common finding in CyCL, especially in PCAETCL. Adnexotropic CyCL may be histopathologically difficult to distinguish from folliculotropic mycosis fungoides. A comprehensive IHC panel should be routinely performed in such cases.

Genomic landscape of cutaneous follicular lymphomas reveals 2 subgroups with clinically predictive molecular features.

Primary cutaneous follicle center lymphomas (PCFCLs) are indolent B-cell lymphomas that predominantly remain skin restricted and manageable with skin-directed therapy. Conversely, secondary cutaneous involvement by usual systemic follicular lymphoma (secondary cutaneous follicular lymphoma [SCFL]) has a worse prognosis and often necessitates systemic therapy. Unfortunately, no histopathologic or genetic features reliably differentiate PCFCL from SCFL at diagnosis. Imaging may miss low-burden internal disease in some cases of SCFLs, leading to misclassification as PCFCL. Whereas usual systemic FL is well characterized genetically, the genomic landscapes of PCFCL and SCFL are unknown. Herein, we analyzed clinicopathologic and immunophenotypic data from 30 cases of PCFCL and 10 of SCFL and performed whole-exome sequencing on 18 specimens of PCFCL and 6 of SCFL. During a median follow-up of 7 years, 26 (87%) of the PCFCLs remained skin restricted. In the remaining 4 cases, systemic disease developed within 3 years of diagnosis. Although the SCFLs universally expressed BCL2 and had BCL2 rearrangements, 73% of the PCFCLs lacked BCL2 expression, and only 8% of skin-restricted PCFCLs had BCL2 rearrangements. SCFLs showed low proliferation fractions, whereas 75% of PCFCLs had proliferation fractions >30%. Of the SCFLs, 67% had characteristic loss-of-function CREBBP or KMT2D mutations vs none in skin-restricted PCFCL. Both SCFL and skin-restricted PCFCL showed frequent TNFRSF14 loss-of-function mutations and copy number loss at chromosome 1p36. These data together establish PCFCL as a unique entity with biological features distinct from usual systemic FL and SCFL. We propose 3 criteria based on BCL2 rearrangement, chromatin-modifying gene mutations (CREBBP, KMT2D, EZH2, and EP300), and proliferation index to classify cutaneous FL specimens based on the likelihood of concurrent or future systemic spread.

Multiple melanocytic nevi restricted to mycosis fungoides patches in pediatric and young-adult patients. The potential role of local immunosuppression.

We described the development of multiple melanocytic nevi within long-standing MF patches in four young patients. Mycosis fungoides (MF) patches are characterized by a regulatory-like cytokine profile leading to local immune suppression. The proliferation of nevomelanocytes is regulated by cellular senescence mechanisms mediated by immune system. The immunosuppressive effect of MF infiltrate in conjunction with the systemic effect of treatments may play a specific role in the nevomelanogenesis of the patients herein described.

Are MicroRNAs Key to Developing Biomarkers for Cutaneous T-Cell Lymphoma?

MicroRNAs are noncoding molecules that induce epigenetic modulation, and they have been involved in tumorigenesis of solid and hematologic malignancies, including cutaneous T-cell lymphoma. MicroRNAs appear to play a role in cutaneous T-cell lymphoma pathogenesis and in disease progression. We comment on recent efforts to develop microRNA classifiers that improve cutaneous T-cell lymphoma diagnosis and predict disease course.

Pruritus in Cutaneous T-Cell Lymphoma and Its Management.

Pruritus is a common symptom in cutaneous T-cell lymphoma (CTCL) and critically affects the quality of life of patients. Understanding the pruritogenesis has led to development of new therapeutic agents with promising outcomes in management of this recalcitrant symptom. Clinical assessments are warranted to aid in evaluation of treatment response or disease recurrence. Severe pruritus scores may require further investigation of emotional distress for a better patient approach. Dermatologists play a key role in the treatment of CTCL-pruritus by guiding the patient in the importance of preserving the integrity of the skin barrier.

Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B-Cell Lymphoma, Leg Type.

Cutaneous diffuse large B-cell lymphomas (DLBCLs) are aggressive lymphomas with a poor prognosis. To elucidate their genetic bases, we analyzed exome sequencing of 37 cutaneous DLBCLs, including 31 DLBCLs, leg type (DLBCL-LT) and 6 cutaneous DLBCLs-not otherwise specified (DLBCL-NOS). As reported previously, 77% of DLBCL-LT harbor NF-κB-activating MYD88 mutations. In nearly all MYD88-wild-type DLBCL-LT, we found cancer-promoting mutations that either activate the NF-κB pathway through alternative genes (NFKBIE or REL) or activate other canonical cancer pathways (BRAF, MED12, PIK3R1, and STAT3). After NF-κB, the second most commonly mutated pathway putatively enables immune evasion via mutations predicted to downregulate antigen processing (B2M, CIITA, HLA) or T-cell co-stimulation (CD58). DLBCL-LT have little genetic overlap with the genetically heterogeneous DLBCL-NOS. Instead, they resemble primary central nervous system and testicular large B-cell lymphomas (primary central nervous system lymphomas and primary testicular lymphomas). Like primary central nervous system lymphomas/primary testicular lymphomas, 40% of DLBCL-LT (vs. 0% of DLBCLs-not otherwise specified) harbored PDL1/PDL2 translocations, which lead to overexpression of PD-L1 or PD-L2 in 50% of the cases. Collectively, these data broaden our understanding of cutaneous DLBCLs and suggest novel therapeutic approaches (e.g., BRAF or PI3K inhibitors). Additionally, they suggest novel treatment paradigms, wherein DLBCL-LT can be targeted with strategies (e.g., immune checkpoint blockers) currently being developed for genomically similar primary central nervous system lymphomas/primary testicular lymphomas.

Progression of undiagnosed cutaneous lymphoma after anti-tumor necrosis factor-alpha therapy.

BACKGROUND: Cutaneous lymphoma diagnosed after anti-tumor necrosis factor-α therapy (anti-TNF-α) has been reported in the literature, yet a clear link between both events remains elusive. OBJECTIVE: To review our experience with cutaneous lymphoma diagnosed during or after the use of anti-TNF-α therapies. METHODS: This is a multicenter retrospective study and a literature review. RESULTS: A total of 22 cases, including 20 cutaneous T-cell lymphomas (CTCLs) and 2 cutaneous B-cell lymphomas, were identified. In the CTCL group, 75% of the patients received an anti-TNF-α agent for a presumed inflammatory skin condition. Mycosis fungoides and Sézary syndrome were the most common subtypes of CTCL diagnosed. Advanced disease (stage IIB to IVA) was commonly seen at time of diagnosis and required aggressive therapy, including stem cell transplant in 3 patients; 2 patients in whom cutaneous B-cell lymphomas was diagnosed had an indolent course. A total of 31 cases were gathered from a literature search. LIMITATIONS: This is a retrospective study. CONCLUSIONS: Our findings suggest that the disease of most of the identified patients was misdiagnosed as psoriasis or eczema; therefore, a comprehensive morphologic and molecular review of skin biopsy specimens and peripheral blood samples should be considered before initiation of anti-TNF-α therapy in patients with poorly defined dermatitis or atypical presentations of psoriasis.

CD8+ mycosis fungoides: A low-grade lymphoproliferative disorder.

BACKGROUND: The prognosis of the CD8+ subtype of mycosis fungoides (MF) is controversial. Although most authors believe that determining the presence of this cell surface antigen has no prognostic value, others have observed a more indolent course for CD8+ MF compared with CD4+ MF. OBJECTIVES: To review the cases of CD8+ MF in the pediatric and adult populations seen at our institution. METHODS: This is a retrospective review of clinical and pathologic data. Age, stage at presentation, and outcomes of patients at our institution were compared with those of 2 large MF cohorts that predominantly were CD4+ from the relevant literature. RESULTS: Sixty-seven patients of a median age of 46 years were included. A higher frequency of early-stage disease was observed for CD8+ MF patients at diagnosis when compared with other cohorts, including 31 (47%) patients with stage IA, 33 (50%) with stage IB, and 2 (3%) with stage IIB (P = .001, P = .001, and P = .002, respectively). With a median follow-up (5.5 years, range 0.2-21 years) similar to other cohorts, a higher rate of complete remission was achieved (65.5%, P = .001), and a lower rate of progression was observed (P = .004). LIMITATIONS: This is a retrospective review. CONCLUSION: Our experience with CD8+ MF confirms a more indolent course of disease with this MF variant. Our results warrant a conservative treatment approach limited to skin-directed therapies and observation in most patients.

Cutaneous T-cell Lymphoma and Pruritus: The Expression of IL-31 and its Receptors in the Skin.

Approximately 88% of cutaneous T-cell lymphoma (CTCL) patients are affected by pruritus that responds poorly to current antipruritic therapies. Interleukin (IL)-31, a Th2 cytokine, has been found to be increased in the serum of CTCL patients and to correlate with itch severity. This study investigated the role of IL-31 and its receptors (IL-31 receptor-alpha [IL-31RA] and OSMRß) in the skin of CTCL patients with mild versus moderate/severe pruritus. Expression levels of IL-31, IL-31RA, and OSMRß in the skin were measured using immunohistochemistry and correlated to pruritus severity and disease stage. In CTCL patients with moderate/severe pruritus, IL-31 was significantly elevated in the epidermis and dermal infiltrate, while IL-31RA and OSMRß were significantly elevated only in the epidermis. Furthermore, epidermal IL-31 levels correlated to itch severity. These results show that IL-31 may play a role in CTCL pruritus by exerting indirect effects on sensory nerves through epidermal neoplastic T cells and keratinocytes to transmit itch.

Single-Fraction Radiotherapy for CD30(+) Lymphoproliferative Disorders.

OBJECTIVES: CD30(+) lymphoproliferative disorder is a rare variant of cutaneous T-cell lymphoma. Sustained complete response following first-line treatments is rare. This retrospective review evaluates the response of refractory or recurrent lesions to palliative radiation therapy. METHODS: The records of 6 patients with 12 lesions, treated with radiation therapy, were reviewed. All patients received previous first-line treatments. Patients with clinical and pathological evidence of symptomatic CD30(+) lymphoproliferative disorder, with no history of other cutaneous T-cell lymphoma variants, and with no prior radiation therapy to the index site were included. RESULTS: The median age of patients was 50.5 years (range, 15-83 years). Median size of the treated lesions was 2.5 cm (range, 2-7 cm). Four sites were treated with a single fraction of 750-800 cGy (n = 3) and 8 sites were treated with 4000-4500 cGy in 200-250 cGy fractions (n = 3). Radiation therapy was administered with electrons and bolus. Median follow-up was 113 months (range, 16-147 months). For all sites, there was 100% complete response with acute grade 1-2 dermatitis. CONCLUSIONS: For recurrent and symptomatic radiation-naïve CD30(+) lymphoproliferative disorder lesions, palliative radiation therapy shows excellent response. A single fraction of 750-800 cGy is as effective as a multifractionated course and more convenient.

Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model.

PURPOSE: Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. PATIENTS AND METHODS: Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). RESULTS: Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). CONCLUSION: To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.

CD30(+) cutaneous lymphoproliferative disorders with pseudocarcinomatous hyperplasia are associated with a T-helper-17 cytokine profile and infiltrating granulocytes.

BACKGROUND: The pathogenetic mechanism of CD30(+) cutaneous lymphoproliferative disorders (CLPD) associated with pseudocarcinomatous hyperplasia (PCH) and granulocytic inflammation surrounding atypical CD30(+) lymphocytes remains unclear. OBJECTIVE: We sought to characterize clinical and pathological findings of a cohort of patients with PCH associated with CD30(+) CLPD and to analyze the cytokine profile of the atypical lymphocytes. METHODS: We retrospectively reviewed medical records and pathological material of CD30(+) CLPD with PCH. Immunohistochemistry for T-helper (Th)17 cytokine profile was performed. RESULTS: In all, 25 patients with a median age of 52 years were included. The median follow-up was 3.7 years. Histologically, an infiltrating pattern of PCH was observed in 14 cases with a neutrophilic-rich infiltrate (P = .21), and epidermal pattern in 11 cases with eosinophil-rich infiltrate (P = .03). Th17 or Th22 cytokines were detected in tumor cells in 81% cases tested. Tumor cells expressed Th17 transcription factor retinoic acid receptor (ROR)-related orphan receptor gamma-2 in 2 of 7 samples tested and 1 was positive for aryl hydrocarbon receptor. LIMITATIONS: This is a retrospective study of a small sample. CONCLUSIONS: PCH in CD30(+) CLPD is associated with Th17/Th22 cytokine expression in the atypical lymphocytes. Although these lesions commonly regress spontaneously and are associated with an indolent course, some cases develop a generalized process and tumor progression.

High incidence of gastrointestinal tract disorders and autoimmunity in primary cutaneous marginal zone B-cell lymphomas.

IMPORTANCE: To our knowledge, this is the first comprehensive study addressing comorbidities associated with primary cutaneous marginal zone B-cell lymphomas (PCMZLs). OBJECTIVE: To determine if patients with PCMZL were at risk for other medical conditions. DESIGN, SETTING, AND PARTICIPANTS: Case-control study at a cutaneous lymphoma clinic and a dermatopathologic consultation service at a single academic institution using an extensive questionnaire of illnesses, symptoms, and environmental exposures for 80 sequential patients with PCMZL and 80 matched controls. MAIN OUTCOMES AND MEASURES: The frequency of several morbidities was obtained in both groups from data gathered from the questionnaire and corroborated by reviewing medical records when available. RESULTS: We found a high incidence of past or present gastrointestinal tract problems in 49 patients (61.2%) with PCMZL compared with 30 participants (37.5%) in the control group (CG) (P = .003). Gastroesophageal reflux was reported in 50.0% (40 vs 27 in the CG, P = .04) and gastric ulcers in 10.0% (8 vs 3 in the CG, P = .13); 20.0% of the cohort had positive Helicobacter pylori serology (16 vs 2 in the CG, P = .003). Colon disorders, including irritable bowel syndrome and inflammatory bowel disease, were more common in the PCMZL cohort (20 vs 7 in the CG, P = .01). Autoimmunity was reported in 20.0% of participants (16 vs 6 in the CG, P = .03). Eight patients had a history of Hashimoto thyroiditis. Three patients had a positive antinuclear antibody. Two had a diagnosis of lupus erythematosus and 1 had Sjögren syndrome. Sicca syndrome was noted in 12.5% (10 vs 3 in the CG, P = .052). A history of noncutaneous malignant neoplasms was observed in 21.3% of the patients (17 vs 8 in the CG, P = .050). Other notable morbidities did not reach statistical significance. CONCLUSIONS AND RELEVANCE: Our results indicate a high incidence of systemic conditions in patients with PCMZL, especially involving the gastrointestinal tract, but also autoimmunity and cancer.

Swimming pool contact dermatitis caused by 1-bromo-3-chloro-5,5-dimethyl hydantoin.

BACKGROUND: Bromo-3-chloro-5,5-dimethylhydantoin (BCDMH) is a chemical used as a disinfectant for recreational water. BCDMH was described as being responsible for an epidemic of irritant contact dermatitis in the UK (1983), and its sensitizing capacity was also discussed. OBJECTIVES: The aim of this study was to assess whether BCDMH used to disinfect swimming pools and spas can cause allergic contact dermatitis among its users. METHODS: Ten patients suffering from dermatitis associated with using swimming pools disinfected with BCDMH and 40 controls were studied. Several dilutions of BCDMH, 10% to 1 ppm, were patch tested. RESULTS: All 10 patients studied showed a positive patch test reaction to BCDMH 1% in petrolatum. At least one case showed occupational relevance, with a positive reaction even at 1 ppm. CONCLUSION: On the basis of the clinical findings, the positive patch test reactions to BCDMH, and the negative patch test reactions in controls, the suggested diagnosis was allergic contact dermatitis caused by BCDMH used as a disinfectant in the swimming pool water. Contact allergy should be taken into consideration when patients suffer from swimming pool-associated itchy dermatitis.