Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorders (SMPLPD), demographical, clinical, therapeutic and prognostic aspects: a retrospective monocentric analysis.

Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorders (SMPLPD), also known as PCS-TCLPD, represent a rare group of hematologic diseases primarily affecting the skin. In this retrospective single-centre case series study, we aimed to investigate the demographic, clinical, therapeutic, and prognostic aspects of SMPLPD. We collected data from cases diagnosed between 2010 and the present, employing histopathological and immunohistochemical methods following WHO criteria. We included 22 patients with a median age of 61.50 years and median time between clinical onset and diagnosis of 3.00 months. Surgical excision with conservative margins was the primary choice, showing clinical remission in 17 cases, while non-surgical treatments, including radiotherapy, high-potency steroid treatment and ablative laser, achieved clinical remission in four cases. Clinical presentations varied, but the most common one was a single violaceous nodule/papule on upper body parts. In conclusion, our single-centre case series provides valuable insights into SMPLPD, highlighting the effectiveness of surgical treatments and the potential of non-surgical ones. Even if controversial, the benign nature of SMPLPD emphasizes the importance of achieving tumour clearance with acceptable aesthetic outcomes.

The Role of Cytokines in Cutaneous T Cell Lymphoma: A Focus on the State of the Art and Possible Therapeutic Targets.

Cutaneous T cell lymphomas (CTCLs), encompassing mycosis fungoides (MF) and Sézary syndrome (SS), present a complex landscape influenced by cytokines and cellular responses. In this work, the intricate relationship between these inflammatory proteins and disease pathogenesis is examined, focusing on what is known at the clinical and therapeutic levels regarding the most well-known inflammatory mediators. An in-depth look is given to their possible alterations caused by novel immunomodulatory drugs and how they may alter disease progression. From this narrative review of the actual scientific landscape, Interferon-gamma (IFN-γ) emerges as a central player, demonstrating a dual role in both promoting and inhibiting cancer immunity, but the work navigates through all the major interleukins known in inflammatory environments. Immunotherapeutic perspectives are elucidated, highlighting the crucial role of the cutaneous microenvironment in shaping dysfunctional cell trafficking, antitumor immunity, and angiogenesis in MF, showcasing advancements in understanding and targeting the immune phenotype in CTCL. In summary, this manuscript aims to comprehensively explore the multifaceted aspects of CTCL, from the immunopathogenesis and cytokine dynamics centred around TNF-α and IFN-γ to evolving therapeutic modalities. Including all the major known and studied cytokines in this analysis broadens our understanding of the intricate interplay influencing CTCL, paving the way for improved management of this complex lymphoma.

New insights into the oncological risk in heart transplant recipients: could skin tumors represent a marker of increased risk for solid neoplasm?

BACKGROUND: Solid organ transplant recipients are at increased risk for skin cancers due to immune-suppressive therapies. However, little is known about the risk and the characteristics of neoplasms in heart transplant recipients (HTRs). The aim of this study is to delineate the incidence of different skin tumors in HTRs and to correlate it with the incidence of other malignancies, including solid tumors and hematological neoplasms. METHODS: Patients who underwent to HTRs between January 1991 and November 2021 were retrieved. Clinical data on immunosuppressive therapies, skin tumors, solid and hematological neoplasms were obtained. HTRs with skin tumors were included in group A, while patients with no evidence of skin tumors during the follow-up were included in group B. RESULTS: One hundred and eight patients were retrieved. A significant increase in solid tumors was observed in group A, while no significant difference in hematological neoplasms was detected between the two groups. CONCLUSIONS: HTRs with skin tumors showed a significantly higher incidence of solid neoplasms. In most of the cases the skin tumor preceded the onset of the solid neoplasm, suggesting that the skin tumor could represent a 'marker' of immunosuppression eventually leading to the development of an internal malignancy.

PD-1 and PD-L1 expression in mycosis fungoides and Sézary Syndrome.

BACKGROUND: The mechanisms involved in mycosis fungoides, and Sezary Syndrome progression are largely unknown. Over the last decade the interest in immune system contrast of neoplasm has grown owing to the introduction of immunotherapy. PD-1 and its ligand (PD-L1) are the target of several immunotherapy treatment. In the literature reports on the expression of PD-1 and PD-L1 have provided contrasting results. METHODS: In our analysis we investigated PD-1 expression in neoplastic cells and in tumor infiltrating lymphocytes (TILs) as well as PD-L1 expression in tumor cells and in tumor associated macrophages (TAMs). PD-L1 and PD-1 positive cells were counted in 5 high-power fields (HPF) and scored as the average number of positive neoplastic cells/TILs/TAMs per HPF. RESULTS: From databases of two institutions (Bologna and Florence) thirty-five patients corresponding to 43 biopsies were retrieved. In seven instances sequential biopsies were present. No statistically significant expression was observed comparing early to advanced stages by analysing PD-1 by tumor cells and TILs and of PD-L1 by tumor cells and TAMs. CONCLUSIONS: Our results corroborate that PD-1 and PD-L1 expression is not stage-dependent in mycosis fungoides and Sezary syndrome. However, PD-1 and PD-L1 expression in affected patients provides a rationale to schedule anti PD-1/PD-L1 drugs.

Erythroderma: psoriasis or lymphoma? A diagnostic challenge and therapeutic pitfall.

BACKGROUND: Psoriasis and lymphoma risk is widely debated, but few is known about misdiagnosis risk between erythrodermic psoriasis and lymphoma. In fact, erythroderma might represent a clinical presentation of psoriasis, cutaneous T-cell lymphomas and skin dissemination of systemic lymphomas. METHODS: All patients referred to psoriasis outpatient service with a diagnosis of erythrodermic psoriasis were re-examined. Among them, all the patients with a subsequent lymphoma diagnosis were included. For each patient data concerning age, gender, age at erythroderma onset, age at lymphoma diagnosis, immune-suppressive therapy, type of lymphoma and relative stage, lymphoma treatment and outcome were obtained. RESULTS: Twenty-five patients (15 females and 10 males) with a diagnosis of erythrodermic psoriasis were retrieved. Among them, 9 patients (5 males and 4 females) were affected by erythrodermic lymphoma, including 4 patients with Sèzary Syndrome, 3 with mycosis fungoides, and 2 with peripheral T-cell lymphoma not otherwise specified. Prior to lymphoma diagnosis all the patients (9/9) received cyclosporine, two (2/9) of them methotrexate, one (1/9) azatioprine, and two (2/9) systemic corticosteroids. The prognosis of our patients was poor, due to immune-suppressive drugs administration in patients with undiagnosed lymphoma. The only exception was one (1/9) patient with Sèzary Syndrome still alive with disease after 120 months of follow-up. CONCLUSIONS: In case of patients with erythroderma, multiple skin biopsies and specific peripheral blood studies like flow cytometry and T-cell receptor gene rearrangement analysis are required in order to avoid misdiagnosis risk between psoriasis and lymphoma.

Biological therapy in patients with psoriasis: What we know about the effects on renal function.

Psoriasis is a chronic inflammatory dermatosis affecting 2%-3% of the general population. The link between psoriasis and renal dysfunction has been investigated, demonstrating a common pro-inflammatory pathogenesis. This study is aimed at evaluating renal function in patients with moderate-to-severe chronic plaque psoriasis treated with biological therapy. We analyzed 92 patients, correlating PASI and serum creatinine levels at baseline, after 6 months and after 1 year of continuous treatment with biological therapy. Data were analyzed using paired t-test and the linear mixed model for PASI and serum creatinine levels correlation, whereas the analysis of variances (ANOVA) was used for creatinine levels assessment between the baseline, the 6-months and, 1-year later evaluation. We observed a significant mean decrease in comparing serum creatinine levels after 1 year of biological therapy (p < 0.001). Interestingly, PASI reduction is correlated with creatinine decrease, and the renal function improvement is greater when complete psoriasis remission is attained. Our data suggest that a drop in systemic inflammation, secondary to biological therapy administration, might improve renal function. Future research is needed to confirm and expand our findings.

The Microenvironment's Role in Mycosis Fungoides and Sézary Syndrome: From Progression to Therapeutic Implications.

BACKGROUND: Mycosis fungoides (MF) and Sezary Syndrome (SS) are the most common cutaneous T-cell lymphomas. It has been hypothesized that the interaction between the immune system, cutaneous cells, and neoplastic elements may play a role in MF/SS pathogenesis and progression. METHODS: This paper aims to revise in a narrative way our current knowledge of the microenvironment's role in MF/SS. RESULTS AND CONCLUSIONS: Literature data support a possible implication of microenvironment cells in MF/SS pathogenesis and progression, opening up new therapeutic avenues.

Immune Check Point Inhibitors in Primary Cutaneous T-Cell Lymphomas: Biologic Rationale, Clinical Results and Future Perspectives.

Primary cutaneous T-cell lymphomas (PCTCL) are the most common types of cutaneous lymphomas, with Mycosis fungoides as the most frequent subtype. Besides early stages which usually have a good prognosis, advanced stages remain a great therapeutic challenge with low survival rates. To date, none of the currently available therapeutic options have significantly improved the outcomes of advanced cutaneous lymphomas. Recent studies have demonstrated that immune-checkpoint molecules, such as PD-1 and CTLA-4, play part in the proliferation pathways of neoplastic T-cells, as well as in other tumors. Hence, the potential role of immune-checkpoint-inhibitors in treating cutaneous lymphomas has been investigated in the last years. Herein, we outline the current knowledge regarding the role of immune-checkpoint molecules in PCTCL, their signaling pathways, microenvironment and therapeutic inhibition rationale. Moreover, we review the published data on immunotherapies in PCTCL and summarize the currently ongoing clinical trials in this field.

Vulvar vitiligo and lichen sclerosus in children: A clinical challenge.

Vulvar vitiligo (VV) and vulvar lichen sclerosus (VLS), both feature skin and mucosal hypo-/depigmentation. The aim of this study was to describe the clinical and dermoscopic features of VV and VLS in the pediatric population, providing diagnostic clues, and to define their association. We performed a systematic literature review of the clinical and dermoscopic features of pediatric VV and VLS. An observational study was conducted on children affected by VLS associated with VV, referred to the Dermatology Unit of the Sant'Orsola Polyclinic in Bologna, Italy. Medical history, age at diagnosis, ethnicity, clinical and dermoscopic features, and symptoms were recorded for all patients. 124 cases of VLS and 10 cases of VV were reviewed. Clinical manifestations included hypo-/depigmented patches in both conditions, while ecchymosis/purpura and fissures/erosion were observed in VLS. Symptoms including pruritus, pain, or burning were reported only by VLS patients. In our study five patients with VLS associated with VV were retrieved. Clinical features included well-demarcated depigmented patches in VV and translucent areas, erythema, ecchymoses/purpura, and labial fusion in VLS. Dermoscopy showed white structureless areas with a whipped cream-like appearance, linear or dotted vessels, white chrysalis-like structures, erosion and red-purpuric blotches in VLS and reduced pigment network or pigment absence, intralesional spots of residual pigmentation and telangiectasias in VV. Symptoms were present in all patients. Both VV and VLS show hypo-/depigmented patches. In the presence of associated symptoms, possible VLS should be investigated with clinical and dermoscopic examination to achieve a prompt diagnosis.

PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis.

Germline PTEN pathogenic variants cause a spectrum of disorders collectively labeled PTEN Hamartoma Tumor Syndrome (PHTS) and featured by hamartomas, developmental anomalies and increased cancer risk. Studies on experimental models provided evidence that PTEN is a "haploinsufficient" tumor-suppressor gene, however, mechanisms involved in the pathogenesis of clinical manifestations in PHTS patients remain elusive. Beyond analyzing clinical and molecular features of a series of 20 Italian PHTS patients, we performed molecular investigations to explore the mechanisms involved in the pathogenesis of PTEN-associated manifestations, with special focus on mucocutaneous manifestations. Typical mucocutaneous features were present in all patients assessed, confirming that these are the most important clue to the diagnosis. The most frequent were papules located in the trunk or extremities (73.7%), oral mucosa papules (68.4%), acral/palmoplantar keratosis and facial papules (both 57.9%), according with literature data. Molecular analyses on one trichilemmoma suggested that the wild-type PTEN allele was retained and expressed, reinforcing the evidence that PTEN does not require a second somatic hit to initiate pathogenic processes. Unexpectedly, one patient also displayed a cutaneous phenotype consistent with atypical mole/melanoma syndrome; no variants were detected in known melanoma genes, but Whole Exome Sequencing showed the rare truncating variant c.495G>A in the CDH13 gene that might have cooperated with PTEN-haploinsufficiency to generate such phenotype. Our findings confirm the reproducibility of known PHTS manifestations in real-world practice, highlighting the role of mucocutaneous manifestations in facilitating prompt diagnosis of the syndrome, and provide some insights into the pathogenic process induced by PTEN alterations, which may contribute to its understanding.