Position paper on a simplified histopathological classification of basal cell carcinoma: results of the European Consensus Project.

BACKGROUND: Histopathological classification of basal cell carcinoma (BCC) has important prognostic and therapeutic implications, but reproducibility of BCC subtyping among dermatopathologists is poor. OBJECTIVES: To obtain a consensus paper on BCC classification and subtype definitions. METHODS: A panel of 12 recognized dermatopathologists (G12) from nine European countries used a modified Delphi method and evaluated 100 BCC cases uploaded to a website. The strategy involved five steps: (I) agreement on definitions for WHO 2018 BCC subtypes; (II) classification of 100 BCCs using the agreed definitions; (III) discussion on the weak points of the WHO classification and proposal of a new classification with clinical insights; (IV) re-evaluation of the 100 BCCs using the new classification; and (V) external independent evaluation by 10 experienced dermatopathologists (G10). RESULTS: A simplified classification unifying infiltrating, sclerosing, and micronodular BCCs into a single "infiltrative BCC" subtype improved reproducibility and was practical from a clinical standpoint. Fleiss' κ values increased for all subtypes, and the level of agreement improved from fair to moderate for the nodular and the unified infiltrative BCC groups, respectively. The agreement for basosquamous cell carcinoma remained fair, but κ values increased from 0.276 to 0.342. The results were similar for the G10 group. Delphi consensus was not achieved for the concept of trichoblastic carcinoma. In histopathological reports of BCC displaying multiple subtypes, only the most aggressive subtype should be mentioned, except superficial BCC involving margins. CONCLUSIONS: The three BCC subtypes with infiltrative growth pattern, characteristically associated with higher risk of deep involvement (infiltrating, sclerosing, and micronodular), should be unified in a single group. The concise and encompassing term "infiltrative BCCs" can be used for these tumors. A binary classification of BCC into low-risk and high-risk subtypes on histopathological grounds alone is questionable; correlation with clinical factors is necessary to determine BCC risk and therapeutic approach.

Lesional activation of Tc 17 cells in Behçet disease and psoriasis supports HLA class I-mediated autoimmune responses.

BACKGROUND: Behçet disease (BD) presents with lymphocytic and neutrophilic vasculitis of unknown aetiology. HLA-B*51, the endoplasmic reticulum aminopeptidase 1 (ERAP1), and interleukin 23 receptor (IL23R)/IL12R are genetic risk factors. IL-23 regulates IL-17A, which controls the recruitment and activation of neutrophils. OBJECTIVES: To determine pathological changes in BD skin lesions related to the complex genetic predisposition. METHODS: We characterized the expression of IL-17A and IL-23A in various cell types by immunohistological double staining of sections from papulopustular skin lesions of acute attacks of BD and psoriasis vulgaris lesions, another HLA-class I-associated T-cell-mediated autoimmune disease in which excessive T-cell-derived IL-17A production promotes neutrophil activation. RESULTS: We found that in BD lesions, as in psoriasis, actively expanding CD8+ T cells were the predominant source of IL-17A. IL-17A+ CD8+ T (Tc 17) cells outnumbered infiltrating IL-17A+ CD4+ T cells. Unlike the epidermal localization of CD8+ T cells in psoriasis, Tc 17 cells in BD lesions mainly infiltrated the perivascular tissue and the blood vessel walls of dermis and subcutaneous tissue. They co-localised with a marked IL-23A expression by CD11c+ dendritic cells and CD68+ macrophages. IL-17A expression was associated with extensive recruitment of neutrophils around blood vessels that formed neutrophil extracellular traps (NETs). CONCLUSIONS: In BD, the genetic predisposition may mediate antigen-specific activation and differentiation of a Tc 17 response, possibly targeting endothelial (auto)antigens. Neutrophils recruited by IL-17A in this process may enhance tissue damage by extensive NET formation (NETosis). Thus, the IL-23/IL-17 axis presumably controls neutrophilic inflammation in BD vasculitis in the context of a predominant antigen-specific CD8+ T-cell response.

Interferon alfa-2a maintenance after salvage autologous stem cell transplantation in atypical mycosis fungoides with central nervous system involvement.

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma with unfavourable prognosis for patients with advanced stages of the disease. Refractory disease and advanced-stage disease require systemic therapy. We report on a rare case of an atypical predominantly CD8+ folliculotropic MF, a subtype of MF with poorer prognosis, in a 59-year-old woman. She was initially diagnosed with MF restricted to the skin, of T3N0M0B0/stage IIB according to the current World Health Organization-European Organisation for Research and Treatment of Cancer classification. First-line treatment with local percutaneous radiotherapy in combination with systemic interferon alfa-2a resulted in complete remission. However, 21 months later the disease progressed to T3N0M1B0/stage IVB with development of cerebral manifestation and thus very poor prognosis. Allogeneic stem cell transplantation (SCT) was not a therapeutic option due to the lack of a suitable donor. We initiated methotrexate and cytarabine chemotherapy, followed by high-dose chemotherapy with thiotepa and carmustine with autologous SCT. Despite rapid response and complete remission of the cerebral lesions, disease recurrence of the skin occurred soon after. Interestingly, readministration of interferon alfa-2a as a maintenance treatment after the salvage autologous SCT resulted in a durable complete remission during the follow-up period of currently 17 months after autologous SCT. What's already known about this topic? Mycosis fungoides is a primary cutaneous T-cell lymphoma with unfavourable prognosis for the advanced stages of the disease. A refractory course of disease requires systemic therapy. What does this study add? We report on an unusual case of a patient with mycosis fungoides with cerebral involvement, in which a durable complete remission was achieved upon autologous stem cell therapy and interferon alfa-2a maintenance therapy.

Histiocytosis - cutaneous manifestations of hematopoietic neoplasm and non-neoplastic histiocytic proliferations.

Histiocytoses are rare disorders characterized by the accumulation of cells derived from macrophages, dendritic cells or monocytes in various tissues. There is a broad spectrum of disease manifestations with some subtypes commonly showing skin lesions, while in others, the skin is rarely involved. Here, we describe cutaneous manifestations of histiocytoses belonging to the Langerhans group (L group), the group of cutaneous and mucocutaneous histiocytoses (C group) and the group of Rosai-Dorfman disease (RDD) and related histiocytoses (R group) according to the current classification. Characteristic clinical presentations noted were a rust-brown colour or xanthomatous aspect in many cases of histiocytoses. Histological criteria for differentiation are described. Immunohistochemistry shows positivity for S100 and CD1a in Langerhans-cell histiocytoses (LHCH) of the L group, while CD68 positivity with S100 and CD1a negativity are typical in histiocytoses of the C group of cutaneous and mucocutaneous histiocytoses. RDD in the R group shows positivity for S100 and CD68, while CD1a is negative. We further review the pathogenesis of LHCH based on insights on the central role of the mitogen-activated protein (MAPK) kinase pathway. Common mutations in various histiocytic populations of diverse ontogeny and at different stages of differentiation may be responsible for the diverse clinical picture of this neoplastic entity. For histiocytoses of the C group and R group, a reactive origin is discussed with the exception of the disseminated form of juvenile xanthogranuloma. We suggest exploring the role of an origin from skin residing histiocytes for the isolated cutaneous manifestation in some types. With regard to therapeutic options, skin-directed therapies are the first choice in limited disease, while systemic chemotherapy has traditionally been used in extensive disease. In Langerhans-cell histiocytoses and related entities, therapy by BRAF inhibition has led to a breakthrough especially in patients with an activation of the MAPK pathway.

Canakinumab in adults with steroid-refractory pyoderma gangrenosum.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare, neutrophilic, ulcerative skin disease that is difficult to treat, especially when unresponsive to steroids. OBJECTIVES: To determine whether canakinumab is an effective and safe treatment in PG. METHODS: Five adult patients with clinically and histologically confirmed steroid-refractory PG were enrolled in this prospective open-label study. They received canakinumab 150 mg subcutaneously at week 0 with an optional 150 mg at week 2 in case of an inadequate response [Physician's Global Assessment (PGA) ≥ 2], and an optional 150-300 mg at week 8 depending on PGA. The primary clinical end point was clinical improvement (PGA at least -1 from baseline) and/or complete remission (PGA 0 or 1) at week 16. Real-time quantitative polymerase chain reaction was performed on skin samples to quantify cytokine mRNA levels. RESULTS: Interleukin (IL)-1ß and its known target genes IL6, CXCL8 and IL36A were significantly increased in lesional skin of PG. Under canakinumab therapy, four of five patients showed a decrease in target-lesion size, PGA and Dermatology Life Quality Index (DLQI), and three of five achieved complete remission. The mean diameter of target lesions decreased from 4·32 ± 2·6 cm at visit 1 to 0·78 ± 1·3 cm at visit 7 (P = 0·03). Mean DLQI decreased from 15 ± 5 at visit 1 to 8 ± 4 by visit 7 (P = 0·01). Adverse effects were reported in two patients: fatigue in one and worsening of disease at a nontarget lesion in the other. CONCLUSIONS: Our data indicate that IL-1ß plays a key pathogenic role in PG and canakinumab may represent a therapeutic option for steroid-refractory PG.

Cerebral toxoplasmosis in an adolescent post allogeneic hematopoietic stem cell transplantation: successful outcome by antiprotozoal chemotherapy and CD4+ T-lymphocyte recovery.

Toxoplasmosis is a rare opportunistic infection in pediatric allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients and associated with severe T-cell deficiency. Here, we report the successful management of cerebral toxoplasmosis in a 15-year-old adolescent 4 months post allo-HSCT for non-Hodgkin lymphoma through rapid invasive diagnostics, long-term antiprotozoal chemotherapy, and an hematopoietic stem cell boost for persistently poor graft function. While supportive care and antiprotozoal chemotherapy achieved stabilization, definite improvement only occurred following recovery of CD4(+) T lymphocytes to >100 cells/µL. At 5 years after the diagnosis of toxoplasmosis, the patient is in continuing remission with normalized clinical and imaging findings.

Paediatric cutaneous lymphomas: a review and comparison with adult counterparts.

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.

Systemic corticosteroids for subcutaneous panniculitis-like T-cell lymphoma.

BACKGROUND: Primary cutaneous γ/δ T-cell lymphoma (PCGD-TCL) is aggressive and has a poor prognosis. In contrast, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) of the α/ß T-cell receptor phenotype is known to follow an indolent course and have a more favourable prognosis. In the past, PCGD-TCL and SPTCL were often considered to be a manifestation of the same disease, and aggressive systemic polychemotherapy has commonly been the first-line therapy for both. Given the understanding that SPTCL is a separate and less aggressive entity, clinical data exclusively evaluating the efficacy of conservative treatment in SPTCL are needed. OBJECTIVES: To assess the overall clinical response to systemic corticosteroids in the treatment of SPTCL. METHODS: This was a retrospective cross-sectional study based on a patient data repository from two tertiary care university hospitals in Zürich (Switzerland) and Tübingen (Germany). The repository spanned 13 years. RESULTS: In four of the five patients (80%) with SPTCL, treatment with systemic corticosteroids induced a complete remission. CONCLUSIONS: Systemic corticosteroids may be an excellent first-line single-agent therapy for SPTCL.

Feasibility of intensive multimodal therapy in infants affected by rhabdoid tumors - experience of the EU-RHAB registry.

Rhabdoid tumors mainly affect infants and other very young children with a marked vulnerability towards intensive therapy such as invasive surgery, high dose chemotherapy (HDCT) and dose intense radiotherapy. Radiotherapy (RT) is a promising option in rhabdoid tumors but its application in infants remains controversial. Neurocognitive and vascular side effects occur even long after completion of therapy. Therapeutic recommendations suggested by the European Rhabdoid Registry including RT, high dose chemotherapy (HDCT) and methotrexate (MTX) were developed by a consensus committee. Unique to our EU-RHAB database is the ability to analyze data of 64 of 81 registered infants (under one year of age) separate from older children. 20 (age at diagnoses 2-12 months) of these had received radiotherapy. To our knowledge, this is the first report specifically analyzing treatment data of infants suffering from malignant rhabdoid tumors. Our results suggest that radiotherapy significantly increases the mean survival time as well as the 3 year overall survival in infants. We detected a doubling of survival times in infants who received RT. Overall, our results suggest that infants benefit from RT with tolerable acute side effects. Severe long term sequelae likely due to intraventricular MTX and/or RT were reported in 4 patients (leukoencephalopathy). No differences in chemotherapy-related toxicity were observed between infants and children. We suggest that a nihilistic therapeutic approach towards young infants is not warranted and that RT may not be a priori rejected as a therapeutic option in infants.

Expression of programmed death-1 (CD279) in primary cutaneous B-cell lymphomas with correlation to lymphoma entities and biological behaviour.

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.

Cutaneous peripheral T-cell lymphomas, unspecified/NOS and rare subtypes: a heterogeneous group of challenging cutaneous lymphomas.

Cutaneous peripheral T-cell lymphoma, unspecified/not otherwise specified (PTL NOS) represents a phenotypically and prognostically heterogenous group of cutaneous T-cell lymphomas (CTCL) that do not fit into any of well defined defined CTCL subtypes. In the WHO-EORTC classification as well as the WHO classification, three entities have been delineated as provisional rare subtypes of PTL based on their characteristic clinico-pathological, immunophenotypic and prognostic features and have been separated out from PTL, NOS: Primary cutaneous CD4-positive small/medium T-cell lymphoma (CD4+ SMTL), primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma (CD8+ AECTCL), and primary cutaneous gamma/delta T-cell lymphoma (CGD-TCL). CD4+ SMTL manifests in most patients with a solitary nodule in the head and neck area and nodular infiltrates of CD4+ small to medium-sized lymphocytes with nuclear pleomorphism. The prognosis of this lymphoproliferation is excellent in patients with a solitary lesion, but may be impaired in patients with multifocal disease. Rapidly evolving erosive or necrotic plaques and nodules with an epidermotropic infiltrate of CD8+ atypical lymphocytes are the hallmark of CD8+ AECTCL, which exhibits a poor prognosis. CGD-TCL displays a broad spectrum of clinical and histological manifestations with expression of the T-cell receptor gamma/delta chain as the common denominator and diagnostic marker. As most of other forms of PTL, CGD-TCL carries a poor prognosis. Despite the rarity of PTL NOS, clinicians as well as dermatopathologists and pathologists should be familiar with these rare CTC, especially since most of these lymphomas exhibit an unfavourable prognosis. Immediate intense treatment with multiagent chemotherapy and hematopoietic stem cell transplantation is indicated in patients with PTL NOS. This review focuses on the clinicopathological aspects, the diagnostic criteria and the classification of the rare subtypes of PTL and PTL NOS.

Catheter-associated aspergillosis of the chest wall following allogeneic hematopoietic stem cell transplantation.

Invasive aspergillosis (IA) at the insertion site of central venous catheters is a rare event. Here we report the occurrence of chest wall aspergillosis at the insertion site of a Broviac catheter in a 5-year-old child undergoing allogeneic hematopoietic stem cell transplantation. The infection arose during profound granulocytopenia under conditions of reverse isolation with laminar air flow and high efficiency particulate air filtration and was successfully managed with repeat surgical debridement, voriconazole/caspofungin combination therapy guided by therapeutic drug monitoring, and adjunctive use of granulocyte colony-stimulating factor. The case reflects the occurrence of IA despite reverse isolation and air decontamination, the principles of treatment of Aspergillus soft tissue infections in granulocytopenic patients, and the need for therapeutic drug monitoring of voriconazole particularly in young children.

Diagnostic pitfall: pigmented lesion of the nipple--correlation between dermoscopy, reflectance confocal microscopy and histopathology.

We present an unusual case of a nevus of the nipple changing during pregnancy which caused a diagnostic pitfall. Nevi on the nipple and areola are infrequent, and diagnostic criteria for clinical, dermoscopy or reflectance confocal microscopy examination for nevi in this 'special location' are still missing. We comment on the literature on dermoscopic findings in mammary lesions and their management during pregnancy, as well as the challenging histopathology of nevi along the milk line. Finally, we focus on two main limitations of reflectance confocal microscopy: the misinterpretation of dendritic cells and the limitation of the imaging depth.

Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group.

The rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pathogenic variants (PV) in genes encoding constituents of the BAF chromatin remodeling complex, i.e. SMARCB1 (RTPS1) and SMARCA4 (RTPS2). In contrast to other genetic disorders related to PVs in SMARCB1 and SMARCA4 such as Coffin-Siris Syndrome, RTPS1&2 are characterized by a predominance of truncating PVs, terminating transcription thus explaining a specific cancer risk. The penetrance of RTPS1 early in life is high and associated with a poor survival. However, few unaffected carriers may be encountered. Beyond RT, the tumor spectrum may be larger than initially suspected, and cancer surveillance offered to unaffected carriers (siblings or parents) and long-term survivors of RT is still a matter of discussion. RTPS2 exposes female carriers to an ill-defined risk of small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT), which may appear in prepubertal females. RT surveillance protocols for these rare families have not been established. To address unresolved issues in the care of individuals with RTPS and to propose appropriate surveillance guidelines in childhood, the SIOPe Host Genome working group invited pediatric oncologists and geneticists to contribute to an expert meeting. The current manuscript summarizes conclusions of the panel discussion, including consented statements as well as non-evidence-based proposals for validation in the future.

Cutaneous angiosarcoma: own experience over 13 years. Clinical features, disease course and immunohistochemical profile.

BACKGROUND: Cutaneous angiosarcoma (AS) is a rare malignant tumour of endothelial origin with very poor prognosis, frequent recurrences and high metastatic potential. Clinical suspicion is often raised too late, but histological findings and immunohistochemical assays have proved to be very helpful in the diagnostic process. PATIENTS AND METHODS: Over the last 13 years, nine patients with AS were found in our archives. Clinical features, evolution, treatment and outcome were analysed and all biopsy specimens were reviewed by a trained dermatopathologist, with subsequent immunohistochemical assessment. RESULTS AND CONCLUSIONS: Cutaneous AS was clinically diagnosed in 4 of 9 patients, while systemic lupus erythematosus was the most common misdiagnosis. Radiotherapy was the most prescribed treatment, but many different combinations of surgery, chemotherapy and radiotherapy were observed. Mean disease-free and overall survival (15.4 and 23.7 respectively) were consistent with previous series, with local recurrence rate (2/9) lower than previously reported data. CD31 was positive in all patients. Vimentin, D2-40 and VEGFR-3 were expressed by the vast majority, Factor VIII by 3/7 and CD34 by about 1/3 of patients. Cytokeratin was negative in all patients. The patients with the most unfavourable course showed a strong expression of Ki-67, while those with the best outcome only had a slight positive Ki-67 staining. Larger studies regarding tumour cell expression of Ki-67 and other markers such as D2-40 will be helpful to evaluate a potential prognostic value of these stainings.

Bortezomib-induced skin eruption.

Bortezomib (Velcad) is a proteasome inhibitor recently developed and mainly used for the treatment of multiple myeloma. Bortezomib represents a novel class of drugs functioning as proteasome inhibitors. Skin complications of bortezomib treatment are very frequent but poorly characterized. We describe the case of a patient who developed erythematous and edematous plaques after treatment with bortezomib. This case illustrates one of the potential reactions associated with bortezomib administration and underlines the need to recognize and report cutaneous side effects of this new drug.