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Background: Interferon-alpha is an important therapeutic option for the treatment of the cutaneous T-cell lymphomas (CTCL). Since the approved recombinant interferon-α-2a (IFN-α2a) has no longer been produced since January 2020, pegylated interferon-α2a (pegIFN-α2a) can be used as an alternative treatment, even though it is not approved for the treatment of CTCL. The aim of this multicentre study was to generate comprehensive data on the efficacy and tolerability of pegIFN-α2a in the treatment of CTCL., Patients and Methods: A multicenter retrospective study was conducted with 70 patients with CTCL from twelve German skin centers., Results: In total, 70 patients were included in the study, with 57.2% male and a mean age of 58.8 ± 14.9 years. Mycosis fungoides was present in 71.4% of cases and Sézary Syndrome in 28.6%. An overall response rate of 55.2% was observed with pegIFNα-2a therapy. In 50% of cases, therapy was discontinued after 63.6 ± 33.5 weeks. The most common reason for discontinuation was adverse events, which occurred in 68.6% of cases and which were classified as severe in 29.2%. Blood count changes, fatigue and liver toxicity occurred most frequently., Conclusions: Our analysis provides comprehensive data on the efficacy and tolerability of pegIFNα-2a therapy in patients with CTCL. In terms of response rates and side effect profile, pegIFNα-2a appears to be comparable to IFN-α2a therapy., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) is a subtype of cutaneous B-cell lymphoma with unfavorable prognosis usually requiring aggressive polychemotherapy for disease control. Only single cases of spontaneous regression of PCDLBCL, LT are reported in the literature, peaking 3 months post-biopsy following a clinical history of no longer than 1 year. Here, we report the first case of a spontaneously relapsing and remitting PCDLBCL, LT with complete regression after a clinical history of more than 9 years and thus an atypically indolent clinical course. The female patient presented with recurrent erythematous, non-ulcerated, non-raised plaques of the right lower leg for 6 years. Pathological workup and exclusion of a systemic disease confirmed the diagnosis of PCDLBCL, LT. Due to the history of repeated spontaneous remission, no therapy was initiated. Nine years after first occurrence the patient presented with complete clinical remission lasting for 64 months. We retrospectively identified four additional PCDLBCL, LT patients with spontaneous remission lasting up to 53 months. Our data provide evidence for a distinct PCDLBCL, LT patient subgroup that clinicians should be aware of and warrants a watch-and-wait treatment regime., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

The classification of primary cutaneous lymphomas and lymphoproliferative disorders (LPD) is continuously evolving by integrating novel clinical, pathological and molecular data. Recently two new classifications for haematological malignancies including entities of cutaneous lymphomas were proposed: the 5th edition of the WHO classification of haematolymphoid tumours and the International Consensus Classification (ICC) of mature lymphoid neoplasms. This article provides an overview of the changes introduced in these two classifications compared to the previous WHO classification. The main changes shared by both classifications include the downgrading of CD8+ acral T-cell lymphoma to CD8+ acral T-cell LPD, and the recognition of entities that were previously categorized as provisional and have now been designated as definite types including primary cutaneous small or medium CD4+ T-cell LPD, primary cutaneous gamma/delta T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, Epstein-Barr virus-positive mucocutaneous ulcer. Both classifications consider primary cutaneous marginal zone B-cell clonal neoplasm as an indolent disease but use a different terminology: primary cutaneous marginal zone lymphoma (WHO) and primary cutaneous marginal zone LPD (ICC). The 5th WHO classification further introduces and provides essential and desirable diagnostic criteria for each disease type and includes chapters on reactive B- or T-cell rich lymphoid proliferations formerly referred as cutaneous pseudolymphomas, as well as histiocyte and CD8 T-cell rich LPD in patients with inborn error of immunity. As already emphasized in previous lymphoma classifications, the importance of integrating clinical, histological, phenotypic and molecular features remains the crucial conceptual base for defining cutaneous (and extracutaneous) lymphomas., (© 2024 European Academy of Dermatology and Venereology.)

Background: Lymphomatoid papulosis (LyP) is a rare cutaneous T-cell lymphoproliferative disorder. Comprehensive data on LyP in the paediatric population are scarce., Objectives: To characterize the epidemiological, clinical, histopathological and prognostic features of paediatric LyP., Methods: This was a retrospective multicentre international cohort study that included 87 children and adolescents with LyP diagnosed between 1998 and 2022. Patients aged ≤ 18 years at disease onset were included. LyP diagnosis was made in each centre, based on clinicopathological correlation., Results: Eighty-seven patients from 12 centres were included. Mean age at disease onset was 7.0 years (range 3 months-18 years) with a male to female ratio of 2 : 1. Mean time between the onset of the first cutaneous lesions and diagnosis was 1.3 years (range 0-14). Initial misdiagnosis concerned 26% of patients. LyP was most often misdiagnosed as pityriasis lichenoides et varioliformis acuta, insect bites or mollusca contagiosa. Erythematous papules or papulonodules were the most frequent clinical presentation. Pruritus was specifically mentioned in 21% of patients. The main histological subtype was type A in 55% of cases. When analysed, monoclonal T-cell receptor rearrangement was found in 77% of skin biopsies. The overall survival rate was 100%, with follow-up at 5 years available for 33 patients and at 15 years for 8 patients. Associated haematological malignancy (HM) occurred in 10% of cases (n = 7/73), including four patients with mycosis fungoides, one with primary cutaneous anaplastic large cell lymphoma (ALCL), one with systemic ALCL and one with acute myeloid leukaemia. If we compared incidence rates of cancer with the world population aged 0-19 years from 2001 to 2010, we estimated a significantly higher risk of associated malignancy in general, occurring before the age of 19 years (incidence rate ratio 87.49, 95% confidence interval 86.01-88.99)., Conclusions: We report epidemiological data from a large international cohort of children and adolescents with LyP. Overall, the disease prognosis is good, with excellent survival rates for all patients. Owing to an increased risk of associated HM, long-term follow-up should be recommended for patients with LyP., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Abstract: Histologic differentiation between melanoma in situ in chronically sun-damaged skin (CSDS) [lentigo maligna (LM)] and CSDS without malignancy is difficult because signs of melanocyte activation and proliferation are found in both. A potentially reliable and quantifiable criterion is melanocyte density (MD). Here, we evaluated whether and to what extent MD allows the distinction between LM and CSDS, which is particularly relevant for the evaluation of borderline cases and surgical margins.Articles assessing MD in LM and/or CSDS were evaluated in a systematic review. The results were categorized and compared according to staining. Cutoff values were included whenever stated.Twenty articles matched the selection criteria. Six hundred forty-four samples of CSDS and 227 samples of LM were considered. In each individual study, mean MD scores were higher for LM than for CSDS. However, looking at the overall study situation, it becomes clear that the data are very heterogeneous and show overlaps. Therefore, no reliable orientation value can be derived. Only 1 article defined a cutoff value.The data of MD in LM in contrast to CSDS were sparse, and a defined cutoff value was only mentioned in 1 article for microphthalmia-associated transcription factor, which cannot yet be generalized. Especially regarding the importance for the definition of surgical resection margins, this unsatisfactory data set highlights the need for further studies. More precise diagnostic criteria could spare some patients extensive and possibly disfiguring surgery., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Lymphomatoid papulosis (LyP) has several histopathologic presentations. LyP featuring gamma-delta (γδ) T-cell receptor expression may masquerade as and may be misdiagnosed as aggressive cutaneous T-cell lymphoma, particularly primary cutaneous γδ T-cell lymphoma (PCGDTL) or γδ mycosis fungoides. We performed a clinicopathologic analysis of the largest series of LyP featuring γδ T-cell expression. We identified 26 patients with a diagnosis of LyP with γδ T cells from our institutions, as well as through a comprehensive review of the literature, and characterized these cases. Most cases were treated with topical steroids or not treated at all. The majority of cases showed a CD4 - CD8 + phenotype and featured at least one cytotoxic marker. Histopathologic features included an intraepidermal or dermal infiltrate with large cells and frequent angiotropism. One case was initially misdiagnosed as PCGDTL, requiring further therapy. Our case series, the largest international cohort of γδ T cell predominant LyP cases, confirms marked clinicopathologic heterogeneity that may contribute to misdiagnosis, reasserting the need to identify classic clinical features, CD30 + T-cell components, and markers of cytotoxicity when dealing with this differential diagnosis. A limitation of this study includes somewhat limited follow-up, histologic, and immunophenotypic information for some cases., Competing Interests: Conflicts of Interest and Source of Funding: A.L.F. receives research funding from Seattle Genetics, is an inventor of technology for which Mayo Clinic holds an unlicensed patent, and has intellectual property licensed to Zeno Pharmaceuticals. A.A.G. is an investigator for StemLine Therapeutics, Innate Pharma, and Dren Bio. He is also consultant for Kyowa Kirin and BluePrints Medicine. For the remaining authors none were declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Primary cutaneous B-cell lymphomas (CBCL) are a group of rare malignant skin diseases that represent approximately 20%-30% of all primary cutaneous lymphomas (PCL). Previous studies revealed impaired health-related quality of life (HRQoL) in patients diagnosed with primary cutaneous T-cell lymphoma (CTCL). Currently, only small-sized studies investigated HRQoL in CBCL patients and lacked detailed analysis of respective subtypes., Objectives: This study aims to investigate HRQoL in CBCL patients to identify independent factors of HRQoL impairment in CBCL patients., Methods: One hundred CBCL patients were recruited from eight German PCL centres in this multicentric, cross-sectional study from 2021 to 2022. The patients completed the dermatologic HRQoL questionnaire Skindex-29 and an investigator-designed 'CBCL-Questionnaire' with additional questions on HRQoL and clinical characteristics., Results: The Skindex-29 revealed that HRQoL in CBCL patients is impaired on a mild to moderate level. The multiple regression analysis identified parameters like worries about dying, feeling prejudiced/discriminated and impairment of daily activities to be independently associated with impairment of HRQoL. Highest scores for HRQoL impairment were found in patients with primary cutaneous follicle centre lymphoma while on rituximab treatment and in patients with primary cutaneous marginal zone lymphoma while on watchful waiting., Conclusions: HRQoL is impaired in CBCL patients, even though, in the face of indolent disease course and favourable prognosis in the majority of cases. Of note, our investigator-designed tool identified worries about dying, feeling prejudiced/discriminated, and the type of treatment to have a negative impact on patients' HRQoL. Our study highlights the importance of a thorough patient-doctor communication to capture overall disease burden because generic HRQoL tools might lack of disease-specific items., (© 2024 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Mycosis fungoides is the most common subtype of cutaneous T-cell lymphoma, in which the expression of cluster of differentiation 30 (CD30)+ subtype can now be treated with the CD30 antibody conjugate brentuximab vedotin. Diagnostic methods are based on immunohistochemical (IHC) staining followed by manual assessment by pathologists, which is always a subjective calculation. QuPath, an open-source software for digital pathology image analysis, satisfies the requirements of objective approaches., Methods: Ten samples from mycosis fungoides patients with CD30 expression at different stages were stained for CD3 and CD30 by IHC staining, scanned, and quantitative analysis was performed using QuPath (version 2.1). Each slide was independently assessed by 3 board-certified dermatopathologists., Results: Individual estimates for CD30+/CD3+ cells varied among the individual histopathologists (mean coefficient of variation, 0.46; range, 0-0.78). QuPath analysis showed excellent separation between the positively stained cells for CD3 and CD30 IHC and other cells and tissue structures, although the results correlated strongly with the respective mean estimates of the 3 histopathologists (Pearson-R 0.93)., Conclusions: The results show a high interobserver variability evaluation of IHC markers, although quantitative image analysis offer a significant advantage for comparison. This is not only relevant for clinical routine but also especially critical in therapeutic studies addressing targeted molecules., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Melanocytic nevi in lymph nodes (NNs) are an important histological differential diagnosis of initial sentinel lymph node (SN) metastasis in melanoma. Our aim was to associate NN in SNs with clinicopathologic features and survival rates in 1, 250 patients with SN biopsy for melanoma., Methods: To compare patients with present and absent NN, we used Fisher's exact test, Mann-Whitney U test, and multivariate logistic regression models in this retrospective observational study based on a prospectively maintained institutional database., Results: NN prevalence in axillary, cervical, and groin SNs was 16.5%, 19.4%, and 9.8%, respectively. NN were observed in combination with all growth patterns of melanoma, but more frequently when the primary was histologically associated with a cutaneous nevus. We observed a decreasing NN prevalence with increasing SN metastasis diameter. Multiple logistic regression determined a significantly increased NN probability for SNs of the neck or axilla, for individuals with ≥ 50 cutaneous nevi, midline primary melanomas, and for individuals who reported non-cutaneous malignancies in their parents. Cancer in parents was also significantly more frequently reported by melanoma patients who had more than 50 cutaneous nevi. In SN-negative patients, NN indicated a tendency for slightly lower melanoma-specific survival., Conclusions: We found a highly significant association between NN diagnosis and multiple cutaneous nevi and provided circumstantial evidence that cutaneous nevi in the drainage area of lymph nodes are particularly important. The trend toward lower melanoma-specific survival in SN-negative patients with NN suggests that careful differentiation of SN metastases is important., (© 2022. The Author(s).)

Aims: To evaluate the frequency, subcellular localization, and variability of CD30 expression in mycosis fungoides., Methods: This retrospective multicenter study investigated 135 biopsy specimens of 95 patients with mycosis fungoides for CD30 expression and CD30 staining pattern in relation to histomorphologic criteria, eosinophils, and tumour stage. We used two different CD30 cutoffs: (i) any CD30 positivity (important for in-label treatment with an anti-CD30 antibody-based drug), and (ii) ≥10% (most commonly used cutoff in therapy studies). The histologic slides were digitally evaluated with a slide viewer. None of the patients were treated with an anti-CD30 antibody-based drug., Results: We found any CD30 expression in 90% of the samples (tumour cells and tumour microenvironment). More than 60% of the samples had CD30 expression ≥10%. CD30 staining was predominantly cytoplasmic and membranous, a Golgi pattern was only found in three samples. In patients with multiple biopsies (69 samples), a highly variable CD30 expression was found, especially in biopsies taken at different timepoints. CD30 and eosinophils were more common in advanced disease stage and cytoplasmic CD30 staining in intraepidermal lymphocytes was significantly associated with the presence of eosinophils., Conclusions: 90% of mycosis fungoides biopsies showed CD30 expression and are principally eligible for anti-CD30-antibody treatment. Because of the high intraindividual variability, investigation of multiple tissue samples for CD30 expression improves the assessment of this therapeutic target. Analysis of only a single skin biopsy might lead to misinterpretation of CD30 and bears the risk of inadequate and potentially unfavourable therapeutic decisions., (© 2022 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Sentinel lymph node (SN) tumor burden is becoming increasingly important and is likely to be included in future N classifications in melanoma. Our aim was to investigate the prognostic significance of melanoma infiltration of various anatomically defined lymph node substructures. This retrospective cohort study included 1250 consecutive patients with SN biopsy. The pathology protocol required description of metastatic infiltration of each of the following lymph node substructures: intracapsular lymph vessels, subcapsular and transverse sinuses, cortex, paracortex, medulla, and capsule. Within the SN with the highest tumor burden, the SN invasion level (SNIL) was defined as follows: SNIL 1 = melanoma cells confined to intracapsular lymph vessels, subcapsular or transverse sinuses; SNIL 2 = melanoma infiltrating the cortex or paracortex; SNIL 3 = melanoma infiltrating the medulla or capsule. We classified 338 SN-positive patients according to the non-metric SNIL. Using Kaplan-Meier estimates and Cox models, recurrence-free survival (RFS), melanoma-specific survival (MSS) and nodal basin recurrence rates were analyzed. The median follow-up time was 75 months. The SNIL divided the SN-positive population into three groups with significantly different RFS, MSS, and nodal basin recurrence probabilities. The MSS of patients with SNIL 1 was virtually identical to that of SN-negative patients, whereas outgrowth of the metastasis from the parenchyma into the fibrous capsule or the medulla of the lymph node indicated a very poor prognosis. Thus, the SNIL may help to better assess the benefit-risk ratio of adjuvant therapies in patients with different SN metastasis patterns., (© 2021. The Author(s).)

Cutaneous T-cell lymphomas (CTCL) represent the majority of primary cutaneous lymphomas (CL). Mycosis fungoides (MF) and cutaneous CD30+ lymphoproliferative disorders account for 80% of all CTCL. CTCL show overlapping histological features. Thus clinical-pathological correlation is of importance to achieve final diagnosis. MF shows a characteristic evolution with patches, plaques, and in a subset of patients (10%-20%) with tumors. Therapy is stage-adapted with skin-directed therapies such as UV-light therapies and corticosteroids in early disease stage (i.e., patch and limited plaque stage) and systemic therapies (retinoids, interferon, mono chemotherapy, targeted therapy) and/or radiation therapy (local or total skin beam electron) in advanced stages. Novel therapies include targeted therapy such as mogamulizumab (anti-CCR4) or brentuximab vedotin (anti-CD30) and histone deacetylase inhibitors. Considering the impact of targeted therapies, biomarkers such as CD30 are not only crucial for the diagnosis and correct classification of an individual lymphoma case, but also for therapy as they may represent therapeutic targets. In the recently revised WHO classification 2017 and the updated WHO-EORTC classification for CL 2018, primary cutaneous CD8+ acral T-cell lymphoma has been introduced as a new still provisional entity. It displays characteristic clinical, histological, and phenotypic features and exhibits an excellent prognosis. Rare, but aggressive CTCL include cutaneous primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma and cutaneous gamma/delta T-cell lymphoma, which present with rapid onset of necrotic or ulcerated plaques and tumors. As they have a poor prognosis, treatment includes multiagent chemotherapy and hematopoietic stem cell transplantation., (© 2021 John Wiley & Sons Ltd.)

Background: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is a prospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) in patients with newly diagnosed mycosis fungoides (MF)., Objectives: To identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB) staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures., Methods: In total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centres in 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review., Results: The most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81·5%), while a smaller percentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariate analysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA, 20%; IA-IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs. T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%, while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improved significantly both in patients with responsive disease and in those with stable disease., Conclusions: Disease characteristics such as presence of plaques and FMF influence physician treatment choices, and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, future treatment guidelines for early-stage MF need to address these issues., (© 2020 British Association of Dermatologists.)

Background: The surface protein CD30 is a therapeutic target of monoclonal antibody therapy. Knowledge of the frequency of CD30 expression and its prognostic relevance is therefore interesting, not only in lymphoproliferative disorders (LPD) but also in solid tumors of the skin., Methods: A review was completed in PubMed for all published reports of CD30 expression in cutaneous lymphomas, mastocytosis, epithelial tumors and sarcomas from 1982 to April 2019. Only accessible articles in English and German were considered. Entities with an expected CD30 expression, such as CD30-positive LPD, were not evaluated., Results: The electronic research identified 1091 articles and a further 34 articles were obtained from manual bibliographic reference. Overall 91 articles were included that examined CD30 expression in various entities of cutaneous neoplasms and matched the inclusion criteria., Conclusion: Apart from cutaneous CD30-positive LPD, the best-studied group for CD30 expression was mycosis fungoides (MF). CD30 positivity was found in 32% of classical (patch and plaque stage) and in 59.4% cases of transformed MF. CD30 was also frequently expressed in cutaneous mastocytosis (96.5%). In solid tumors, some single reports describe CD30 expression by tumor cells, but CD30-reactive lymphocytes were frequently observed in the tumor microenvironment (TME), especially in keratoacanthoma (KA)., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Cutaneous peripheral T-cell lymphoma, not otherwise specified (PTL NOS) is an aggressive, but poorly characterized neoplasm., Objectives: The European Organization for Research and Treatment of Cancer cutaneous lymphoma taskforce (EORTC CLTF) investigated 33 biopsies of 30 patients with primary cutaneous PTL NOS to analyse their clinical, histological, immunophenotypic features and outcome., Methods: Retrospective analysis of clinical data and histopathological features by an expert panel., Results: Cutaneous PTL NOS manifested clinically either with solitary or disseminated rapidly grown ulcerated tumours or disseminated papulo-nodular lesions. Histologically, a mostly diffuse or nodular infiltrate in the dermis and often extending into the subcutis was found. Epidermotropism was rarely present and only mild and focal. Unusual phenotypes were frequent, e.g. CD3 + /CD4 - /CD8 - and CD3 + /CD4 + /CD8 + . Moreover, 18% of the cases exhibited an aberrant expression of the B-cell marker CD20 by the tumour cells. All solitary tumours were located on the limbs and presented a high expression of GATA-3 but this did not correlate with outcome and therefore could not serve as a prognostic factor. The prognosis was shown to be generally poor with 10 of 30 patients (33%) dying of lymphoma within the follow-up of 36 months (mean value; range 3-144). The survival rates were 61% after 3 years (CI, 43-85%) and 54% after 5 years (CI, 36-81%). Small to medium-sized morphology of tumour cells was associated with a better outcome than medium to large or large tumour cells. Age, gender, clinical stage, CD4/CD8 phenotype and GATA-3 expression were not associated with prognosis. Chemotherapy was the most common treatment modality, but surgical excision and/or radiotherapy may represent an appropriate first-line treatment for solitary lesions., Conclusions: Cutaneous PTL NOS shows an aggressive course in most patients independent of initial presentation, age and phenotype. Cytomorphology was identified as a prognostic factor. The data indicate a need for more effective treatment modalities in PTL NOS., (© 2020 European Academy of Dermatology and Venereology.)

Background: Early-stage mycosis fungoides (MF) includes involvement of dermatopathic lymph nodes (LNs) or early lymphomatous LNs. There is a lack of unanimity among current guidelines regarding the indications for initial staging imaging in early-stage presentation of MF in the absence of enlarged palpable LNs., Objectives: To investigate how often imaging is performed in patients with early-stage presentation of MF, to assess the yield of LN imaging, and to determine what disease characteristics promoted imaging., Methods: A review of clinicopathologically confirmed newly diagnosed patients with cutaneous patch/plaque (T1/T2) MF from PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) data., Results: PROCLIPI enrolled 375 patients with stage T1/T2 MF: 304 with classical MF and 71 with folliculotropic MF. Imaging was performed in 169 patients (45%): 83 with computed tomography, 18 with positron emission tomography-computed tomography and 68 with ultrasound. Only nine of these (5%) had palpable enlarged (≥ 15 mm) LNs, with an over-representation of plaques, irrespectively of the 10% body surface area cutoff that distinguishes T1 from T2. Folliculotropic MF was not more frequently imaged than classical MF. Radiologically enlarged LNs (≥ 15 mm) were detected in 30 patients (18%); only seven had clinical lymphadenopathy. On multivariate analysis, plaque presentation was the sole parameter significantly associated with radiologically enlarged LNs. Imaging of only clinically enlarged LNs upstaged 4% of patients (seven of 169) to at least IIA, whereas nonselective imaging upstaged another 14% (24 of 169). LN biopsy, performed in eight of 30 patients, identified N3 (extensive lymphomatous involvement) in two and N1 (dermatopathic changes) in six., Conclusions: Physical examination was a poor determinant of LN enlargement or involvement. Presence of plaques was associated with a significant increase in identification of enlarged or involved LNs in patients with early-stage presentation of MF, which may be important when deciding who to image. Imaging increases the detection rate of stage IIA MF, and identifies rare cases of extensive lymphomatous nodes, upstaging them to advanced-stage IVA2., (© 2020 British Association of Dermatologists.)

Background: The immune checkpoint molecule PD-L1 represents an important target in oncological immune therapy. The aim of our study was to evaluate PD-L1 expression and the composition of the tumor microenvironment (TME) in Kaposi sarcoma., Methods: Immunohistochemical stains were performed for PD-L1, CD3, CD33, CD68, and CD168 in 24 Kaposi sarcoma samples. In PD-L1-positive cases, the double stains for PD-L1, CD31, podoplanin, and HHV8 were added., Results: PD-L1 was observed in 71% of the samples and was predominantly located in the TME. PD-L1 expression was significantly higher in nodular stage than in patch/plaque stage. The TME consisted of CD68+/CD163+ macrophages, CD33+ myloid-derived suppressor cells and monocytes and CD3+ T-cells. The TME showed a peritumoral distribution in nodular stage, in contrast to a diffuse distribution in patch/plaque stage. In 12 samples (50%), no plasma cells were found., Conclusion: In nodular stage of KS, the TME is pushed back in the periphery of the tumor nodules. The PD-L1-positive TME between the tumor cells might protect them from the immune attack. An anti-PD-L1 treatment might be promising in KS patients., (© 2020 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Background: Deep learning convolutional neural networks (CNN) may assist physicians in the diagnosis of melanoma. The capacity of a CNN to differentiate melanomas from combined naevi, the latter representing well-known melanoma simulators, has not been investigated., Objective: To assess the diagnostic performance of a CNN when used to differentiate melanomas from combined naevi in comparison with dermatologists., Methods: In this study, a CNN with regulatory approval for the European market (Moleanalyzer-Pro, FotoFinder Systems GmbH, Bad Birnbach, Germany) was used. We attained a dichotomous classification (benign, malignant) in dermoscopic images of 36 combined naevi and 36 melanomas with a mean Breslow thickness of 1.3 mm. Primary outcome measures were the CNN's sensitivity, specificity and the diagnostic odds ratio (DOR) in comparison with 11 dermatologists with different levels of experience., Results: The CNN revealed a sensitivity, specificity and DOR of 97.1% (95% CI [82.7-99.6]), 78.8% (95% CI [62.8-89.1.3]) and 34 (95% CI [4.8-239]), respectively. Dermatologists showed a lower mean sensitivity, specificity and DOR of 90.6% (95% CI [84.1-94.7]; P = 0.092), 71.0% (95% CI [62.6-78.1]; P = 0.256) and 24 (95% CI [11.6-48.4]; P = 0.1114). Under the assumption that dermatologists use the CNN to verify their (initial) melanoma diagnosis, dermatologists achieve an increased specificity of 90.3% (95% CI [79.8-95.6]) at an almost unchanged sensitivity. The largest benefit was observed in 'beginners', who performed worst without CNN verification (DOR = 12) but best with CNN verification (DOR = 98)., Conclusion: The tested CNN more accurately classified combined naevi and melanomas in comparison with trained dermatologists. Their diagnostic performance could be improved if the CNN was used to confirm/overrule an initial melanoma diagnosis. Application of a CNN may therefore be of benefit to clinicians., (© 2019 European Academy of Dermatology and Venereology.)

Background and Objectives: Combined nevi (CN) show two or more components of major nevus subtypes and simulate melanomas. We investigated a panel of dermoscopic features and three dermoscopic algorithms for differentiating CN from melanomas., Patients and Methods: Retrospective, blinded case-control study using dermoscopic images of 36 CN and 36 melanoma controls. Twenty-one dermoscopic features validated for the diagnosis of melanocytic lesions, the number of colors, and three dermoscopic algorithms were investigated (ABCD rule of dermoscopy, Menzies scoring method, 7-point checklist)., Results: Five of seven features indicative of nevi were observed significantly more frequently in CN than in melanomas (all p < 0.05) and two were exclusively found in CN. Eleven out of 14 features indicative of melanomas were observed significantly more frequently in melanomas than in CN (all p < 0.03) and five were exclusively found in melanomas. The mean (± SD) number of colors in CN was lower than in melanomas (2.1 ± 0.6 versus 3.4 ± 0.7; p < 0.001). Among tested algorithms the ABCD rule of dermoscopy performed best (sensitivity 91.7 %, specificity 77.8 %)., Conclusions: The ABCD rule of dermoscopy differentiated CN from melanomas most efficiently. Additional knowledge of dermoscopic features to be expected exclusively in either CN or melanomas should help dermatologists to make a correct clinical diagnosis., (© 2020 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Cutaneous pseudolymphomas (PSLs) belong to a group of lymphocytic infiltrates that histopathologically and/or clinically simulate lymphomas. Different causative agents (e.g., Borrelia sp., injected substances, tattoo, arthropod bite) have been described, but in many cases no cause can be identified, hence the term idiopathic PSL. Clinicopathological correlation is important to make the diagnosis. Four main groups of cutaneous PSL can be distinguished based on histopathologic and/or clinical presentation: (a) nodular PSL; (b) pseudo-mycosis fungoides (pseudo-MF) and simulators of other CTCLs; (c) other PSL (representing distinct clinical entities); and (d) intravascular PSL. This article gives an overview of the histopathologic and clinical characteristics of cutaneous PSLs and proposes a new classification., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Survival in mycosis fungoides (MF) is varied and may be poor. The PROCLIPI (PROspective Cutaneous Lymphoma International Prognostic Index) study is a web-based data collection system for early-stage MF with legal data-sharing agreements permitting international collaboration in a rare cancer with complex pathology. Clinicopathological data must be 100% complete and in-built intelligence in the database system ensures accurate staging., Objectives: To develop a prognostic index for MF., Methods: Predefined datasets for clinical, haematological, radiological, immunohistochemical, genotypic, treatment and quality of life are collected at first diagnosis of MF and annually to test against survival. Biobanked tissue samples are recorded within a Federated Biobank for translational studies., Results: In total, 430 patients were enrolled from 29 centres in 15 countries spanning five continents. Altogether, 348 were confirmed as having early-stage MF at central review. The majority had classical MF (81·6%) with a CD4 phenotype (88·2%). Folliculotropic MF was diagnosed in 17·8%. Most presented with stage I (IA: 49·4%; IB: 42·8%), but 7·8% presented with enlarged lymph nodes (stage IIA). A diagnostic delay between first symptom development and initial diagnosis was frequent [85·6%; median delay 36 months (interquartile range 12-90)]. This highlights the difficulties in accurate diagnosis, which includes lack of a singular diagnostic test for MF., Conclusions: This confirmed early-stage MF cohort is being followed-up to identify prognostic factors, which may allow better management and improve survival by identifying patients at risk of disease progression. This study design is a useful model for collaboration in other rare diseases, especially where pathological diagnosis can be complex., (© 2018 British Association of Dermatologists.)

AL-amyloidoma is considered to be a variant of primary cutaneous marginal zone lymphoma (pcMZL). A 51-year-old white man presented a 2 × 2-cm erythematous to brownish waxy plaque on the back of the scalp. The plaque was first noticed 16 years ago. It was asymptomatic, and the patient was otherwise healthy. The lesion was excised. Histological examination revealed dermal deposits of amyloid and a subtle perivascular infiltrate, predominately consisting of plasma cells. Infiltrating cells expressed CD79a, bcl2, and IgG and were negative for bcl6, CD56, and IgM. A monoclonal light-chain expression of lambda (lambda:kappa = 10:1) was demonstrated by in situ hybridization. The diagnosis of pcMZL, presenting as an AL-amyloidoma, was made because staging procedures excluded systemic manifestation of lymphoma, monoclonal gammopathy, and systemic amyloidosis. Cutaneous amyloid deposits with monoclonal plasma cell proliferation can occur as a result of monoclonal gammopathy/plasmocytoma or as a rare manifestation of pcMZL. Systemic B-cell lymphoma and systemic monoclonal plasma cell proliferations have to be excluded.

Primary cutaneous lymphomas (CL) are the second most common form of extranodal lymphomas. Cutaneous T-cell lymphomas represent the majority. They are classified according to the WHO classification 2017 and the updated WHO-EORTC 2018 published in the fourth edition of the WHO classification for Skin Tumors monograph. Primary cutaneous acral CD8+ T-cell lymphoma and EBV-positive mucocutaneous ulcer have been listed as new provisional entities. Moreover, the histological and genetic spectrum of lymphomatoid papulosis has been expanded. Recently, prognostic subtypes were delineated for some entities and subtypes of CL such as folliculotropic mycosis fungoides and marginal zone lymphoma. Since CL show overlapping histological features, clinico-pathological correlation is of outmost importance for the diagnosis. Recent studies revealed new biomarkers and genetic alterations underlying the pathogenesis of CL. Moreover, targeted therapies have widened the treatment options particularly for aggressive lymphomas., (© 2019 John Wiley & Sons, Ltd.)

The histopathologic differentiation between Spitz nevus and melanoma is of particular interest in routine diagnostic procedures of melanocytic tumors. Atypical Spitz nevi are sometimes difficult to distinguish from melanoma. There is still no single criterion that ensures a distinction of melanoma and atypical Spitz nevus. The aim of this study was to reevaluate established and new criteria to differentiate Spitz nevus from melanoma more reliably. We analyzed 25 melanomas with a Breslow index ≥ 1 mm and 18 classical compound Spitz nevi concerning their histopathologic, immunohistochemical and molecular genetic characteristics. Moreover, clinical follow-up data for 5 years were collected. We found statistically significant differences between Spitz nevus and melanoma for the following features: pagetoid spread, atypia, maturation, elastosis, Kamino bodies, p16 expression, and the staining pattern of HMB45. BRAF was positive in 7/21 melanomas and in 1/14 Spitz nevi. Fluorescence in situ hybridization confirmed the histopathologic diagnosis in 36/37 cases. The established clinical, histopathologic, and immunohistochemical criteria to differentiate Spitz nevus and melanoma could be reproduced in our collective. Especially, the expression of p16, BRAF analysis and fluorescence in situ hybridization proved to be helpful tools to improve the differentiation of Spitz nevus and melanoma in our study. Nevertheless, there is-until now-no reliable histopathologic and immunohistochemical parameter which can discriminate Spitz nevus and melanoma with absolute certainty.

Cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ LPD) are the second most common form of cutaneous T-cell lymphoma. CD30+ LPD include lymphomatoid papulosis, primary cutaneous anaplastic large-cell lymphoma, and borderline lesions. Despite expression of CD30 by the neoplastic cells as the hallmark of these disorders, they differ in their clinical presentation and histological features as well as the course, the prognosis, and consecutively in the treatment. Diagnosis of CD30+ LPD and distinction from the broad spectrum of differential diagnoses essentially depends on clinicopathologic correlation as well as the results of staging examinations. Although the histological findings indicate a high-grade lymphoma, CD30+ LPD in most cases have a favorable prognosis. Recent advances in targeted therapy have led to new therapeutic approaches to CD30+ LPDs. This review describes the clinicopathologic features of CD30+ LPDs, their differential diagnoses, the treatment, and the role of CD30 as a diagnostic marker and therapeutic target., (©2018 Frontline Medical Communications.)

Background: Merkel cell carcinoma (MCC) is an aggressive neoplasm, which is often associated with Merkel cell polyomavirus (MCPyV). Programmed death-1 (PD-1) and its ligand PD-L1 are key players of the tumor microenvironment (TME)., Methods: Fourteen paraffin-embedded tissue samples of MCC were stratified by their MCPyV detection. Apart from PD-L1 and PD-1, the TME was further characterized for the expression of CD33, FOXP3 and MxA., Results: We observed PD-1 in 2 of 12 tumors. PD-L1 expression by tumor cells was found in 7 of 8 MCPyV(+) samples and was detected particularly in the periphery. The tumor cells were surrounded by a shield of PD-L1/CD33 immune cells. Expression of PD-L1 by the tumor cells was higher in areas with a denser immune infiltrate. CD33(+) cells without direct tumor contact were PD-L1 negative. Only a low number of FOXP3(+) regulatory T-cells was admixed. Tumor cells of MCPyV(-) samples were mostly PD-L1 negative., Conclusions: Our data demonstrate that PD-L1 expression occurs in tumor and immune cells, in areas in which they are close in contact. Interferon seems to play a role in this interaction. We postulate that PD-L1(+)/CD33(+) cells shield the tumor against attacking PD-1(+) immune cells. Therefore, next to anti-PD-1/PD-L1 antibodies, blockade of CD33 seems to be a promising therapeutic approach., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Cutaneous lymphomas are rare skin cancers with a wide clinical spectrum., Objective: To give an overview of the current classification and the clinical spectrum of cutaneous lymphomas., Material and Methods: Analysis and summary of the current literature concerning the different entities of cutaneous lymphomas., Results: A few modifications in the nomenclature of cutaneous lymphoma have been introduced in the revised version of the WHO classification 2016. In the last years new types of lymphomatoid papulosis were described. Moreover, two subgroups of folliculotropic mycosis fungoides are now mentioned. The CD4+ small/medium T‑cell lymphoproliferative disorder is no longer classified as an overt lymphoma. As new entities the EBV+ mucocutaneous ulcer, an EBV-associated diffuse large B‑cell lymphoma (not otherwise specified) and a primary cutaneous acral CD8 + T‑cell (provisional) lymphoma are being considered., Conclusion: The classification of cutaneous lymphomas is based on the revised version of the WHO classification (2016). The clinical pathological correlation is an elementary component for correct diagnosis.

Programmed death ligand 1 (PD-L1) is expressed by 20% to 57% of systemic diffuse large B cell lymphomas (DLBCLs). PD-L1 expression in primary cutaneous DLBCL (pcDLBCL) has not been studied so far. Sixteen paraffin-embedded tissue samples of pcDLBCL (13 leg type [LT], 3 others [OT]) were investigated for PD-1, PD-L1, and CD33 expression and the cellular composition of the tumor microenvironment, focusing on myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages. Membrane-bound PD-L1 expression by the tumor cells was observed in all samples, albeit to a variable extent (19.9%). As expected, most DLBCL-LT (10 cases) were classified as activated B cell like type, with a higher PD-L1 score (21.9%) compared with that of the germinal center B cell like type (7.7%). The surrounding infiltrate consisted predominately of CD163(+) M2 rather than CD68(+) macrophages (CD68:CD163=1:4 to 6). Moreover, a considerable proportion of CD33(+) MDSCs with PD-L1 coexpression was admixed. Tumor cells expressed CD33 to variable degrees (2% to 60%). The number of MDSCs or M2 macrophages did not correlate with pcDLBCL subtypes LT or OT. T cells were only a minor component of the tumor microenvironment. We propose that PD-L1(+) tumor cells and PD-L1(+) MDSCs shield the tumor against PD-1(+) tumor-infiltrating lymphocytes, consequently leading to inhibition and diminution of tumor-infiltrating lymphocytes. Moreover, we found a polarization to M2 macrophages, which may contribute to the poor prognosis of DLBCL patients. Thus, targeting of tumor cells and MDSCs using anti-PD-1/anti-PD-L1 or anti-CD33 antibodies might be a worthwhile new approach to treat this aggressive form of cutaneous B-cell lymphoma.

Clinically, lymphomatoid papulosis (LYP) is characterized by recurrent papulonodular lesions. Unlike this stereotypical clinical presentation, the histological spectrum of LYP is very wide, comprising distinct growth patterns, variably sized neoplastic cells, and different immunophenotypes. The revised 2016 WHO classification includes the histological LYP types A to E as well as another type characterized by a specific chromosomal alteration. In addition, new LYP types are going to be proposed, based not only on histological but also on clinical and genetic features. The ensuing expansion of the alphabetical list of histological types will add to the complexity of the terminology of LYP, thereby potentially increasing the risk of complicating rather than facilitating the diagnostic approach to the disease. Moreover, there may be overlap between individual disease types. This development raises the question as to how to simplify the terminology of LYP while still respecting its histological complexity. Herein, we advocate a practical approach to the terminology of LYP based on descriptive terms rather than the designation of LYP types by alphabetical characters. Our proposal aims to contribute to a pragmatic and user-friendly approach, thus not only facilitating the diagnostic process but also the communication between clinicians and pathologists., (© 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Primary cutaneous lymphomas comprise a prognostically heterogeneous group of lymphocytic skin neoplasms, which display a broad spectrum of clinical, histologic, immunophenotypic, and genetic features. The histopathological examination plays an essential role and is often the starting point in the diagnostic workup of cutaneous lymphomas. In most cases, the histopathological and the phenotypic analysis alone are limited to provide a list of differential diagnoses. As a consequence of overlapping clinical, histologic, phenotypic, and genetic features among several entities of cutaneous lymphomas, the clinicopathological correlation is of utmost importance to achieve the final diagnosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Primary cutaneous lymphomas (CL) in children is rare. Only a few studies focused specifically on paediatric CL and therefore little is known whether primary CL in children are similar to or different from their adult counterparts with respect to the clinicopathological presentation, behaviour and prognosis. An extensive literature search using PubMed/MEDLINE from January 1995 through July 2014 was undertaken for articles reporting cases of paediatric CL. In addition, we identified 31 children with CL in our institutions. Mycosis fungoides and lymphomatoid papulosis are the two most prevalent lymphoma forms in children. A few entities of cutaneous lymphomas such as cutaneous diffuse large B-cell lymphoma leg type, and Sézary syndrome have not been reported so far in children. Other lymphoma entities such as hydroa vacciniforme-like lymphoma are mostly seen in certain geographic areas (Asia, Central and South America). In the paediatric population, low-malignant indolent forms such as primary cutaneous marginal zone lymphoma and primary cutaneous follicle centre lymphoma are very rare, whereas the more aggressive forms of B-cell lymphomas, precursor lymphoblastic lymphomas, and blastic plasmacytoid dendritic cell neoplasm are the most common forms in children, mostly involving the skin secondarily. Most paediatric lymphomas have similar clinicopathological features and course as their adults counterparts, particularly in the group of cutaneous T-cell lymphomas. The spectrum of cutaneous B-cell lymphomas in children significantly differs from the one in adults. Diagnostic work-up and treatment of paediatric patients with lymphomas are best achieved in close collaboration with paediatric haematopathologists and oncologists., (© 2015 European Academy of Dermatology and Venereology.)

Background: In nodal anaplastic large cell lymphoma, strong expression of galectin-3 (Gal-3) has been found, but only very few cases of primary cutaneous lymphoma have so far been examined., Objectives: To investigate 11 primary cutaneous anaplastic large cell lymphomas (PCALCL), 47 lymphomatoid papuloses (LYP) and 14 cases of transformed mycosis fungoides with CD30 expression (MF-T) for Gal-3 expression., Methods: A Gal-3 score was applied using a photo-based morphometric evaluation program. Double staining for CD30 and Gal-3 was performed. Furthermore, we recorded the cellular and extracellular sublocalization of the signal., Results: The Gal-3 expression in CD30+ tumor cells was significantly lower in MF-T in contrast to CD30+ lymphoproliferative disorders (CD30 LPD; p < 0.001), but we found no differences between PCALCL and LYP (p = 0.42). In PCALCL Gal-3 was more often localized in the cytoplasm in contrast to LYP, in which an equal distribution in the cytoplasm and the nucleus was more common (p = 0.9)., Conclusions: The lower Gal-3 expression in MF-T in comparison to CD30 LPD might be an additional criterion to differentiate both entities. The different sublocalization of the Gal-3 signal might reflect a different biological function and behavior.

Background: Sentinel lymph node (SLN) biopsy (SLNB) for pT1 melanomas is not generally recognized as a clinical standard. We studied the value of SLNB for pT1 melanoma patients having at least one additional risk factor., Patients: Among 931 patients with SLNB, 210 had pT1 melanomas. All of the latter showed at least one of the following risk factors: ulceration (4 %) Clark level IV (44 %), nodular growth pattern (11 %), mitoses (59 %), regression (38 %) or age ≤ 40 years (27 %)., Results: In this selected pT1 population, we observed a surprisingly high SLN positivity rate of 18 %. The melanoma-specific overall survival significantly depended on SLN status. Compared with Clark IV, a lower invasion level (Clark II/III) was associated with a higher proportion of positive SLNs (25 vs. 10 %; p < 0.01). There was a trend towards a higher SLN positivity rate in younger patients (p = 0.06). Breslow, ulceration, mitoses, nodular growth pattern, and sex did not reach significance. Regression was significantly more frequently found in very thin melanomas (≤ 0.75 mm) and tended to be significant in this subgroup (p = 0.075)., Conclusions: SLNB improves prognostic stratification in patients with thin melanomas having an additional risk factor. Clark level IV most likely does not belong to these risk factors. The impact of regression deserves further consideration. Our data suggest that SLNB should be offered to patients with thin melanomas, if ulceration, nodular growth pattern, mitoses, or regression are present, or if the patient is younger than 40 years of age.

Head or neck location of primary cutaneous melanomas has been described as an adverse prognostic factor, but this has to be reassessed after the introduction of sentinel lymph node (SLN) excision (SLNE). Descriptive statistics, Kaplan-Meier estimates and Cox proportional hazard models were used to study retrospectively a population of 2302 consecutive melanoma patients from three German melanoma centres undergoing SLNE. Approximately 10% of the patients (N=237) had a primary melanoma located at the head or neck (HNM). In both the SLN-positive and SLN-negative subpopulation, patients with HNM were significantly older, more frequently men and had thicker primaries compared with patients with tumours in other locations. The proportion of positive SLNs was lower in HNM compared with other locations of the primary (20 vs. 26%, P=0.048). The false-negative rate was higher in HNM (17.5 vs. 8.4%, P=0.05). In patients with HNM, the SLN status was a significant factor for recurrence-free survival but not for overall survival. SLN-negative HNM patients had a significantly worse overall survival than the SLN negatives with primaries at other sites, whereas the prognosis of the SLN-positive patients was similar in both groups. The prevalence of lymph node metastases after SLNE is lower in patients with HNM compared with other melanoma locations. As a result, the prognostic information provided by the SLN for HNM seems less important. Decision making for SLNE in HNM should be carefully balanced considering the potential morbidity of the procedure.

: Primary cutaneous B-cell lymphomas (PCBCL) are the second most common form of primary cutaneous lymphomas and account for approximately 25%-30% of all primary cutaneous lymphomas. Both forms of low-grade malignant PCBCL, primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma of mucosa-associated lymphoid tissue-type (MALT lymphoma) (PCMZL) represent the vast majority of PCBCL and show an indolent slowly progressive course and an excellent prognosis despite a high recurrence rate. Genetic analysis indicates that PCMZL differ from other forms of extranodal MALT lymphomas. The more common class-switched and the non-class-switched form of PCMZL can be distinguished as two distinctive subsets that differ in the cellular composition, IgM expression, and biological behavior with extracutaneous involvement found in the non-class-switched form. Recently, unusual clinical and histological forms of PCMZL and PCFCL manifesting with miliary or agminated lesions have been described that are diagnostically challenging. In contrast to PCMZL and PCFCL, primary cutaneous diffuse large B-cell lymphoma, leg type, and other rare forms of large B-cell lymphomas such as intravascular large B-cell lymphoma have an unfavorable prognosis. There is an emerging group of Epstein-Barr virus (EBV)-driven B-cell lymphoproliferations including posttransplant lymphoproliferative disorders and mucocutaneous ulcer occurring in immunocompromised patients and EBV-associated diffuse large B-cell lymphoma of the elderly arising in the setting of senescence-linked immunodeficiency. This review reports on recent findings expanding the spectrum of clinicopathological features, differential diagnostic aspects, and the pathogenesis of PCBCL and discusses the group of EBV-associated B-cell lymphoproliferations involving the skin.

Background: Programmed death-1 (PD-1/CD279) is a cell-surface protein expressed in activated T cells and a subset of T lymphocytes including follicular helper T cells (TFH ). The interaction between PD-1 and its ligands plays a role in immune response and evasion of malignancies. In nodal follicular lymphoma, the number of intratumoral PD-1-positive lymphocytes is associated with overall survival., Objectives: To investigate 28 cases of primary cutaneous B-cell lymphoma, including the subtypes PCFCL (n = 10), PCMZL (n = 10) and DLBCL-LT (n = 8) for the number and density of PD-1-positive cells., Methods: Immunohistochemical staining and a computerized morphometric analysis for evaluation were applied. The results were correlated with the clinical outcome. To distinguish between activated T cells and TFH we performed PD-1/bcl-6 double staining and compared these results with CXCL-13 staining. Double staining for PD-1 and PAX-5 was used to investigate whether tumour cells were positive for PD-1., Results: The PD-1-positive cells represented tumour-infiltrating T cells (TILs). Only a minor subset was represented by TFH . Patients with DLBCL-LT had a significantly lower number of PD-1-positive TILs than those with PCMZL (P = 0·012) and PCFCL (P = 0·002) or both (P = 0·001). The difference between PCMZL and PCFCL did not reach significance (P = 0·074). The tumour cells were negative for PD-1., Conclusions: A higher number of PD-1-expressing cells was found in indolent PCMZL and PCFCL than in high-malignant DLBCL-LT. The PD-1-positive cells represented not only TFH , but also other activated T cells as a part of the tumour microenvironment. The tumour cells in all investigated types of PCBCL did not show aberrant PD-1 expression., (© 2013 British Association of Dermatologists.)

Background: The value of a preoperative lymphoscintigraphy in melanoma patients with clinically evident regional lymph node metastases has not been studied. Therapeutic lymph node dissection (TLND) is regarded as the clinical standard, but the appropriate extent of TLND is controversial in all lymphatic basins., Patients and Methods: Of the 115 consecutive patients with surgery on palpable lymph node metastases, 34 received a pre-operative lymphoscintigraphy. Lymphatic drainage to a second nodal basin outside the clinically involved basin was found in 15 cases. In 13 patients, the ectopic tumor-draining lymph nodes were excised as in a sentinel node biopsy. The lymph nodes from the TLND specimens were postoperatively separated and classified as either radioactive or non-radioactive., Results: A total of 493 lymph nodes were examined pathologically. The largest macrometastasis maintained the ability to take up radiotracer in 77% of cases. Radioactively labeled lymph nodes carried a higher risk of being involved with metastasis. The proportions of tumor involvement for radioactive and non-radioactive lymph nodes were 44.5 and 16.9%, respectively (P=0.00002). Of the 13 ectopic nodal basins surgically explored, six harbored clinically occult metastases., Conclusion: In patients undergoing TLND for palpable metastases, tumor-draining lymph nodes in a second, ectopic nodal basin should be excised, because they could be affected by occult metastasis. With respect to radioactive lymph nodes situated within the nodal basin of the macrometastasis but beyond the borders of a less-radical lymphadenectomy, further studies are needed.

Background: About 10% of patients with Merkel cell carcinoma (MCC) suffer from an associated squamous cell carcinoma (SCC). In European patients, Merkel cell polyomavirus (MCPyV) is detectable in 60%-88% of the MCC tumors. In combined lesions, MCPyV was not detectable so far., Methods: We investigated 2 combined tumors of MCC and SCC for the presence of MCPyV and human papillomavirus (HPV) by polymerase chain reaction and immunohistochemistry., Results: In both lesions, MCPyV DNA was found, and in 1 case, HPV DNA was also detected. This is the first report of a coinfection with HPV and MCPyV in combined MCC-SCC tumors., Conclusions: The results underline the hypothesis of co-cancerogenesis of 2 oncogenic viruses in nonmelanoma skin cancer. Technical reasons and a low viral copy number of MCPyV hampering immunohistochemical detection may be responsible for the negative results in the literature.

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare entity characterized by a CD4+/CD56+/CD123+ immunophenotype and a fatal clinical course. The average survival of 12-14 months may be prolonged by allogeneic bone marrow transplantation (BMT)., Objectives: We report about a male patient who suffered from BPDCN with a typical histology and co-expression of CD4/CD123 and a CD56 expression by 80% of the tumour cells. The cutaneous tumour relapse after chemotherapy and allogeneic BMT was completely negative for CD56., Methods: We performed interphase fluorescence in situ hybridization (FISH) analysis of tumour tissue, asserved before and after BMT, using specific probes for chromosome 11, which encompass the CD56 gene region., Results: The tumour cells revealed a partial loss of 11q as well as a monosomy of chromosome 11., Conclusion: This case demonstrates for the first time that loss of CD56 expression can also occur as a secondary event after chemotherapy and BMT. In our case, DNA loss of 11q23 could be responsible for the negativity of 20% of tumour cells as observed before chemotherapy. However, the complete loss of CD56 expression in the relapsed tumour cannot be explained by the loss of 11q23 alone. Additional factors such as chemotherapy-induced mutations might also have contributed., (© 2010 The Authors. Journal of the European Academy of Dermatology and Venereology © 2010 European Academy of Dermatology and Venereology.)

In our study, we investigated the impact of the constitutional factor age on the clinical courses of melanoma patients with sentinel lymph node (SLN) biopsy. Descriptive statistics, Kaplan-Meier estimates, logistic regression analysis and the Cox proportional hazards model were used to study a population of 2,268 consecutive patients from three German melanoma centers. Younger age was significantly related to less advanced primary tumors. Nevertheless, patients younger than 40 years of age had a twofold risk of being SLN-positive (p < 0.000001). Of the young patients with primary melanomas with a thickness of 0.76 mm to 1.0 mm, 19.7% were SLN-positive. Using multivariate analysis, younger age, increasing Breslow thickness, ulceration and male sex were significantly related to a higher probability of SLN-metastasis. During follow-up, older patients displayed a significantly increased risk of in-transit recurrences (p = 0.000002) and lymph node recurrences (p = 0.0004). With respect to melanoma specific overall survival the patient's age was highly significant in the multivariate analysis. The unfavorable effect of being older was significant in the subgroups with positive and negative SLNs. Age remained also significant for the survival after the onset of distant metastases (p = 0.002). In conclusion, the patient's age is a strong and independent predictor of melanoma-specific survival in patients with localized melanomas, in patients with positive SLNs and after the onset of distant metastases. Younger patients have a better prognosis despite their higher probability of SLN metastasis. Older patients are less frequently SLN-positive but have a higher risk of loco-regional recurrence., (Copyright © 2011 UICC.)

The optimal processing for the pathology of sentinel lymph nodes of patients with melanoma is still a matter of debate. We compared two protocols of sentinel lymph node processing, which were consecutively applied. For the first protocol, the sentinel lymph nodes were cut into 1-2 mm thick slices. From each slice, 12 microtome sections were stained (multiple slices protocol). For the second protocol, which is a modification of the recent European Organisation for Research and Treatment of Cancer protocol, the sentinel lymph nodes were bivalved. Five consecutive series of microtome sections, with gaps of 50 microm between them, were prepared from each cut surface (bivalving protocol). H&E and immunohistochemical staining were integral elements of both protocols. A total of 584 sentinel lymph nodes (1.8+/-0.9 per patient) were examined. The percentages of micrometastases (29 versus 27%) and of capsular naevi (13 versus 15%) detected were very similar for both protocols. As shown by multivariate logistic regression, Breslow thickness (P=0.003) and younger age (P=0.01) correlated with nodal metastasis. The type of histological preparation, ulceration and sex were not significant. The multiple slices protocol produced, on average, 4 paraffin blocks and 46 microtome sections per node. The bivalving protocol constantly produced 2 paraffin blocks and 42 microtome sections. For technical processing, the multiple slices protocol required, on average, 38 min per sentinel lymph node, whereas the bivalving protocol required 55 min. Both protocols yielded excellent detection rates with a similar amount of work being required on the part of the pathologist. Compared with the bivalving protocol, the multiple slices protocol was less labor intensive for the technical staff.

Mycosis fungoides is the most common subtype of mature T-cell lymphoma that primarily arises in the skin. The tumor manifests as patches, plaques, tumors, or erythroderma and can secondarily involve lymph nodes, peripheral blood, and visceral organs. In advanced tumor stage, chemotherapy is a second-line approach, which is generally not considered curative. Initially, most patients profit from this treatment, but observed remissions usually do not exceed several months. Because of possible immunosuppressive effects in vulnerable patients, the overall benefit of chemotherapy itself is not unequivocal in cutaneous T-cell lymphoma. We report 3 patients whose tumor-stage mycosis fungoides was not sufficiently controlled by several preceding systemic therapies, including liposome-encapsulated doxorubicin. All patients experienced excellent improvement with 250 mg/m2 gemcitabine weekly, a low-dose regimen that is predicted to be less toxic compared with standard-dose gemcitabine.

Blastic plasmacytoid dendritic cell (BPDC) neoplasm, formerly called blastic natural killer cell lymphoma or CD4+/CD56+ hematodermic neoplasm, is a rare tumor entity, now regarded to be derived from the plasmacytoid dendritic cell (PDC) lineage. Because over 90% of patients present with skin lesions usually early in their disease, dermatologists have to be familiar with the specific diagnostic features and the clinical course of this devastating disease. We present a woman with a long standing solitary skin tumor of BPDC neoplasm, who experienced a deleterious clinical course, which is typical for this disease. Phenotypic and karyotypic characteristics distinguishing this tumor from myelomonocytic leukemia with skin involvement are presented.