Primary Localized Cutaneous Amyloidosis in Central Europe: A Retrospective Monocentric Study on Epidemiology and Therapy.

Amyloid deposits can be the cause of many chronic diseases. Primary localized cutaneous amyloidosis (PLCA) is a chronic dermatologic condition with amyloid deposits in the papillary dermis. The most common types of the keratinocyte-derived form of PLCA include macular (MA), lichen (LA), and biphasic (BA) amyloidosis. The estimated prevalence of PLCA in the Asian population is 0.98/10,000, which is higher than in the European population; thus, epidemiologic data on PLCA in the Caucasian population are limited. We performed a retrospective single-center study analyzing epidemiologic characteristics of a Central European PLCA population. Epidemiologic data regarding age, sex, skin phototype (Fitzpatrick scale I-VI), disease duration, comorbidities, history of atopy, and family history of PLCA were collected. Clinical characteristics, localization of PLCA lesions, applied therapies and treatment outcomes were also analyzed. Dermoscopic characteristics were also evaluated. A total of 41 patients diagnosed with PLCA were included, with 22 presenting with macular, 18 with lichen, and 1 with biphasic amyloidosis. The male/female ratio was 16/25, and mean age at diagnosis was 54.6 ± 15.2 years (range 27-87 years). The mean age at the onset of PLCA was 53 ± 16.1 years (range 19-79 years) in MA, 46.7 ± 18.2 years (range 14-73 years) in LA, and 26 years in BA. The interscapular region in MA and the extensor surface of the lower extremities in LA proved to be localization-related areas. In our center, a wide range of therapeutic options was applied, with the most prescribed being topical corticosteroids in all types of PLCA. We presented a retrospective, monocentric study on the epidemiology of PLCA in the Central European region. By examining the medical data of a significant number of PLCA patients, we compared our epidemiologic data with that of the Asian PLCA population. Due to the rarity of the condition, further randomized controlled trials and guidelines are needed to improve therapeutic outcomes.

Optically Guided High-Frequency Ultrasound to Differentiate High-Risk Basal Cell Carcinoma Subtypes: A Single-Centre Prospective Study.

BACKGROUND: Basal cell carcinoma (BCC) is the most common type of skin cancer in the Caucasian population. Currently, invasive biopsy is the only way of establishing the histological subtype (HST) that determines the treatment options. Our study aimed to evaluate whether optically guided high-frequency ultrasound (OG-HFUS) imaging could differentiate aggressive HST BCCs from low-risk tumors. METHODS: We conducted prospective clinical and dermoscopic examinations of BCCs, followed by 33 MHz OG-HFUS imaging, surgical excision, and a histological analysis. We enrolled 75 patients with 78 BCCs. In total, 63 BCCs were utilized to establish a novel OG-HFUS risk classification algorithm, while 15 were employed for the validation of this algorithm. The mean age of the patients was 72.9 ± 11.2 years. Histology identified 16 lesions as aggressive HST (infiltrative or micronodular subtypes) and 47 as low-risk HST (superficial or nodular subtypes). To assess the data, we used a one-sided Fisher's exact test for a categorical analysis and a Receiver Operating Characteristic (ROC) curve analysis to evaluate the diagnostic accuracy. RESULTS: OG-HFUS distinguished aggressive BCC HSTs by their irregular shape (p < 0.0001), ill-defined margins (p < 0.0001), and non-homogeneous internal echoes (p = 0.004). We developed a risk-categorizing algorithm that differentiated aggressive HSTs from low-risk HSTs with a higher sensitivity (82.4%) and specificity (91.3%) than a combined macroscopic and dermoscopic evaluation (sensitivity: 40.1% and specificity: 73.1%). The positive and negative predictive values (PPV and NPV, respectively) for dermoscopy were 30.2% and 76.8%, respectively. In comparison, the OG-HFUS-based algorithm demonstrated a PPV of 94.7% and an NPV of 78.6%. We verified the algorithm using an independent image set, n = 15, including 12 low-risk and 3 high-risk (high-risk) with two blinded evaluators, where we found a sensitivity of 83.33% and specificity of 91.66%. CONCLUSIONS: Our study shows that OG-HFUS can identify aggressive BCC HSTs based on easily identifiable morphological parameters, supporting early therapeutic decision making.

Whole genome sequencing resolves 10 years diagnostic odyssey in familiar myxoma.

Carney complex (CNC) is an ultrarare disorder causing cutaneous and cardiac myxomas, primary pigmented nodular adrenocortical disease, hypophyseal adenoma, and gonadal tumours. Genetic alterations are often missed under routine genetic testing. Pathogenic variants in PRKAR1A are identified in most cases, while large exonic or chromosomal deletions have only been reported in a few cases. Our aim was to identify the causal genetic alteration in our kindred with a clinical diagnosis of CNC and prove its pathogenic role by functional investigation. Targeted testing of PRKAR1A gene, whole exome and whole genome sequencing (WGS) were performed in the proband, one clinically affected and one unaffected relative. WGS identified a novel, large, 10,662 bp (10.6 kbp; LRG_514t1:c.-10403_-7 + 265del; hg19, chr17:g.66498293_66508954del) deletion in the promoter of PRKAR1A in heterozygous form in the affected family members. The exact breakpoints and the increased enzyme activity in deletion carriers compared to wild type carrier were proved. Segregation analysis and functional evaluation of PKA activity confirmed the pathogenic role of this alteration. A novel deletion upstream of the PRKAR1A gene was proved to be the cause of CNC. Our study underlines the need for WGS in molecular genetic testing of patients with monogenic disorders where conventional genetic analysis fails.

Real-World Experience with Cemiplimab Treatment for Advanced Cutaneous Squamous Cell Carcinoma-A Retrospective Single-Center Study.

BACKGROUND: The systemic treatment of advanced cutaneous squamous cell carcinoma (cSCC) has seen significant developments in recent years. The anti-PD1 inhibitor cemiplimab has demonstrated efficacy in clinical trials, but real-world data are still limited. Here, we aimed to evaluate the efficacy and the safety of cemiplimab in a real-world clinical setting. METHODS: A retrospective analysis was carried out for all patients who received at least two doses of cemiplimab at our department between February 2020 and January 2023. Progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the disease control rate (DCR) and adverse events (AEs) were evaluated. RESULTS: Twenty-five patients were included with a median age of 78 (65-82) years. The median treatment duration was 48 (16-72) weeks. Five (20%) patients were immunocompromised. Sixteen patients (64%) developed AEs, including 36% serious AEs (SAEs) of grade ≥ 3. Six patients (24%) were withdrawn from treatment due to the occurrence of AEs. Among the 25 patients, 52% showed an objective response (3 complete and 10 partial responses), 76% had controlled disease and 24% experienced progression. Among the five immunocompromised patients, the ORR was 60%, while the DCR was 80%. CONCLUSIONS: This retrospective real-world study revealed that locally advanced or metastatic cSCC could be effectively treated with cemiplimab even in elderly, polymorbid and immunocompromised patients.

Cutaneous malignancies in patients with Parkinson's disease at a dermato-oncological university centre in Hungary.

Background: The possible correlation between melanoma and Parkinson's disease (PD) has been intensively studied. In this work, we aimed to assess the coincidence of skin malignancies and PD at a dermato-oncological university centre in Central-Eastern Europe, Hungary. Methods: From 2004 to 2017, a retrospective analysis of the centre's database was performed based on International Statistical Classification of Diseases-10 codes. Results: Out of the patients who visited the clinic during the study period, 20,658 were treated for malignant skin tumours. Over the 14 years, 205 dermatological patients had PD simultaneously, 111 (54%) of whom had at least one type of skin malignancy: melanoma (n=22), basal cell carcinoma (BCC) (n=82), or squamous cell carcinoma (SCC) (n=36) (in some patients, multiple skin tumours were identified). Compared to the age- and sex-matched control group, patients with PD had a significantly lower risk for basal cell carcinoma (OR, 0.65; 95% CI, 0.47-0.89, p=0.0076) and for all skin tumours (OR, 0.74; 95% CI, 0.56-0.98, p=0.0392) but not for melanoma. Conclusions: We found a decreased risk of all skin tumours and basal cell carcinoma and an unchanged risk of melanoma among patients with PD. However, it should be kept in mind that some large-scale meta-analyses suggest a higher incidence of melanoma after a diagnosis of PD, indicating the importance of skin examination in this vulnerable population.

Scrofuloderma and granuloma annulare-like lesions: Challenges of diagnosing cutaneous tuberculosis in developed countries.

Tuberculosis remains a global health concern, as the increasing levels of urban poverty, higher number of immunodeficient patients and the development of drug resistance threaten the overall efforts made to induce a downward trend for the disease. Scrofuloderma, also known as tuberculosis cutis colliquativa is a subtype of cutaneous tuberculosis. Here we detail a case of a 70-year-old female patient presented with unilateral, left-sided, multiple palpable, painful, ulcerated and purulent cervical nodules, accompanied by persistent generalized erythematous popular granuloma annulare-like skin lesions on the upper extremities. Based on the result of the PCR assay, culture, imaging and histopathological findings, the diagnosis of scrofuloderma was established. To achieve prompt diagnosis and early treatment, it is crucial to include scrofuloderma in the differential diagnosis of ulcerated lesions in developed countries as well, and also be aware of the additional clinical symptoms, such as granuloma annulare-like lesions, possibly accompanying cutaneous tuberculosis.

[Characteristics of the course of lupus erythematosus panniculitis in a retrospective analysis of 17 patients]. / A lupus erythematosus panniculitis lefolyásának jellegzetességei 17 betegünk retrospektív vizsgálata alapján.

INTRODUCTION: Lupus erythematous panniculitis (LEP) is a rare type of chronic cutaneous lupus erythematous. Clinical characteristics are tender, subcutaneous nodules, erythematous plaques. Disfigurement of face and body might develop which affects the patient's quality of life. LEP can be the first sign of systemic lupus erythematous (SLE). OBJECTIVE: Our aim was to review the clinicopathological characteristics and the course of LEP through our own patients. METHODS: We retrospectively analyzed the clinical records of 17 LEP patients at Semmelweis University's Department of Dermatology, Venerology and Dermatooncology between 2000 and 2022. RESULTS: The male : female ratio was 1 : 16, average age was 37.8 years. Lesion localisations were proximal lower (8/17) and upper extremities (7/17), face (4/17), breast (3/17), chest (2/17), buttocks (2/17), back (1/17) and distal lower extremity (1/17). Lesion morphologies were nodules (11/17), plaques (7/17), lipoatrophy (4/17), ulceration (3/17), calcification (1/17). Discoid changes covered in 6 cases. In 10 cases, systemic symptoms were observed (arthritis (4/17), haematological (5/17), renal (2/17), anti-phospholipid syndrome (2/17). 7 patients fulfilled the EULAR/ACR criteria for SLE. Histology showed mixed type panniculitis in 8, lobular in 3 cases. Average time until diagnosis was 24.3 months. Among all our SLE patients, skin symptoms regressed following systemic immunosuppressive treatment. LEP patients with only skin manifestation were often resistant for the therapy of cutaneous lupus erythematous. CONCLUSION: The diagnosis of LEP often takes months or years. Wider knowledge of LEP would shorten the time to diagnosis, preventing disfigurement and possible damage of internal organs. Based on our observations, LEP without SLE might be treated with early immunosuppression. Orv Hetil. 2023; 164(5): 172-178.

Immunohistochemical Study of the PD-1/PD-L1 Pathway in Cutaneous Lupus Erythematosus.

The pathomechanism of various autoimmune diseases is known to be associated with the altered function of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) axis. We aimed to investigate the role of this pathway and inflammatory cell markers in subtypes of cutaneous lupus erythematosus (CLE): discoid lupus erythematosus (DLE), subacute CLE (SCLE) and toxic epidermal necrolysis (TEN)-like lupus, a hyperacute form of acute CLE (ACLE). Ten skin biopsy samples from 9 patients were analyzed with immunohistochemistry regarding the following markers: CD3, CD4, CD8, Granzyme B, CD123, CD163, PD-1, PD-L1. Our group consisted of 4 SCLE (2 idiopathic (I-SCLE) and 2 PD-1 inhibitor-induced (DI-SCLE)), 4 DLE and 1 TEN-like lupus cases. From the latter patient two consecutive biopsies were obtained 1 week apart. Marker expression patterns were compared through descriptive analysis. Higher median keratinocyte (KC) PD-L1 expression was observed in the SCLE group compared to the DLE group (65% and 5%, respectively). Medians of dermal CD4, Granzyme B (GB), PD-1 positive cell numbers and GB+/CD8+ ratio were higher in the DLE group than in the SCLE group. The I-SCLE and DI-SCLE cases showed many similarities, however KC PD-L1 expression and dermal GB positive cell number was higher in the former. The consecutive samples of the TEN-like lupus patient showed an increase by time within the number of infiltrating GB+ cytotoxic T-cells and KC PD-L1 expression (from 22 to 43 and 30%-70%, respectively). Alterations of the PD-1/PD-L1 axis seems to play a role in the pathogenesis of CLE.

Spätmanifeste Kalzinose in Brandnarben: Eine Literaturübersicht und zwei Fallberichte.

Calcinosis cutis, die heterotope Ablagerung von Kalziumsalzen in der Haut, wurde in einigen Fällen als spät auftretende Komplikation von Brandnarben beschrieben. Sie unterscheidet sich diesbezüglich von heterotoper Ossifikation, die eine früh einsetzende Komplikation von Brandverletzungen sein kann. Die Diagnose einer Kalzinose kann radiographisch, sonographisch, computertomographisch, magnetresonanztomographisch oder histologisch bestätigt werden. Nahezu alle Fälle einer spätmanifesten Kalzinose bei Brandnarben imponieren als nicht heilendes Ulkus an den unteren Extremitäten in der Nähe der Kontrakturbänder. Es wird diskutiert, dass diese Lokalisation auf die häufigeren Mikrotraumen an den unteren Extremitäten zurückzuführen ist, und dass die Ulzeration aufgrund der Kalziumablagerungen als Fremdkörper auftritt. In unserer Studie betrug das Durchschnittsalter zum Zeitpunkt der Brandverletzung 12,5 ± 8,27 Jahre und die Kalzinose entwickelte sich im Mittel nach einer Zeitspanne von 37,5 ± 14,95 Jahren (das Durchschnittsalter bei Beginn war 50,5 ± 14,53 Jahre). Es gab keinen signifikanten Unterschied zwischen Brandnarben, die mittels Hauttransplantation behandelt wurden, und solchen, bei denen keine Hauttransplantation durchgeführt wurde. Die Ulzera verheilten nach Resektion oder Extraktion der Ablagerungen ohne Rezidiv an derselben Stelle. Im Gegensatz zu früher gemeldeten Fällen beobachteten wir zwei Fälle einer spät einsetzenden Kalzinose ohne Ulzeration bei Brandnarben an den oberen Extremitäten.

Late-onset calcinosis in burn scars: A review of the literature and two case reports.

Calcinosis cutis is a heterotopic accumulation of calcium salts in the skin. It has been described as a late-onset complication of burn scars in a few cases, in contrast to heterotopic ossification, which may be an early-onset complication of burn injuries. Diagnosis of calcinosis can be confirmed by radiography, ultrasonography, computed tomography, magnetic resonance imaging or histology. Almost all cases of late-onset calcinosis in burn scars present as non-healing ulcers on the lower extremities near contracture bands. It has been hypothesized that this localization is due to the more frequent microtrauma of the lower extremities, and that ulceration is due to the presence of calcium deposits as foreign bodies. In our study, the mean age at the time of burn injury was 12.5 ± 8.27 years, and calcinosis developed after a mean time of 37.5 ± 14.95 years (mean age at onset was 50.5 ± 14.53 years). There was no significant difference between burn scars managed with skin grafting and those where skin grafting was not carried out. The ulcers healed after resection or extraction of the deposits without any recurrence at the same site. In contrast to previously reported cases, we observed two cases of non-ulcerating late-onset calcinosis in burn scars of the upper extremities.

Case report of amyloid light-chain amyloidosis with periocular cutaneous involvement / Periorbitalis bortünetekkel járó könnyulánc-amyloidosis

Összefoglaló. A könnyulánc-amyloidosis ritka, multidiszciplináris jelentoségu kórkép, melynek hátterében az esetek dönto hányadában egy amyloidogen fehérje, a csontvelo kóros plazmasejtjeiben termelodo monoklonálisimmunglobulin-molekula lambda típusú könnyuláncának felszaporodása áll. A klinikai tünetek az érintett szervek függvényében igen változatosak és gyakran nem specifikusak, ezért a betegség sok esetben késon kerül felismerésre. A diagnózis felállításának alapfeltétele a szövettani vizsgálat elvégzése és a kóros fehérjelánc kimutatása. A betegség jellegzetes alarmírozó bortüneteinek helyes értékelése fontos szereppel bír a korai diagnózisalkotásban. A jelen közlemény egy myeloma multiplexhez társult könnyulánc-amyloidosis esetét mutatja be. A betegnél a pathognomicus, típusos borgyógyászati tünetek (periorbitalis, axillaris és inguinalis lokalizációjú petechiák, purpurák, ecchymosisok, suffusiók és viaszsárga papulák) mellett szív- és veseérintettség is igazolódott. Az alkalmazott ciklofoszfamid-, bortezomib- és dexametazonkezelési séma hatására a csontveloben komplett morfológiai remisszió következett be, a beteg a jelenleg legjobb túlélést biztosító autológossejt-transzplantáció elott áll. Orv Hetil. 2021; 162(32): 1303-1308. Summary. Amyloid light-chain amyloidosis is a rare disease with diverse signs and symptoms according to the affected organs. The signs are often aspecific which can lead to delayed diagnosis. Considering the characteristic cutaneous manifestations of the disease, dermatologists have an important role in early identification. Additionally, histopathological examination is required for diagnosis. Here we present a rare case of light-chain amyloidosis in association with multiple myeloma. The patient presented with characteristic periocular, axillar and inguinal petechiae, purpurae, ecchymoses, suffusions, yellowish-brown waxy papules and plaques besides cardiovascular and renal involvement. In this case, the amyloidogenic proteins are the lambda-chains of monoclonal immunoglobulins secreted by the clonally expanded plasma cells of the bone marrow. The applied cyclophosphamide, bortezomib and dexamethason treatment induced complete morphological remission in the bone marrow and the patient currently awaits autologous stem cell transplantation which yields the longest possible survival. Orv Hetil. 2021; 162(32): 1303-1308.

Visualization of Keratin with Diffuse Reflectance and Autofluorescence Imaging and Nonlinear Optical Microscopy in a Rare Keratinopathic Ichthyosis.

Keratins are one of the main fluorophores of the skin. Keratinization disorders can lead to alterations in the optical properties of the skin. We set out to investigate a rare form of keratinopathic ichthyosis caused by KRT1 mutation with two different optical imaging methods. We used a newly developed light emitting diode (LED) based device to analyze autofluorescence signal at 405 nm excitation and diffuse reflectance at 526 nm in vivo. Mean autofluorescence intensity of the hyperkeratotic palmar skin was markedly higher in comparison to the healthy control (162.35 vs. 51.14). To further assess the skin status, we examined samples from affected skin areas ex vivo by nonlinear optical microscopy. Two-photon excited fluorescence and second-harmonic generation can visualize epidermal keratin and dermal collagen, respectively. We were able to visualize the structure of the epidermis and other skin changes caused by abnormal keratin formation. Taken together, we were able to show that such imaging modalities are useful for the diagnosis and follow-up of keratinopathic diseases.

Multispectral Imaging Algorithm Predicts Breslow Thickness of Melanoma.

Breslow thickness is a major prognostic factor for melanoma. It is based on histopathological evaluation, and thus it is not available to aid clinical decision making at the time of the initial melanoma diagnosis. In this work, we assessed the efficacy of multispectral imaging (MSI) to predict Breslow thickness and developed a classification algorithm to determine optimal safety margins of the melanoma excision. First, we excluded nevi from the analysis with a novel quantitative parameter. Parameter s' could differentiate nevi from melanomas with a sensitivity of 89.60% and specificity of 88.11%. Following this step, we have categorized melanomas into three different subgroups based on Breslow thickness (≤1 mm, 1-2 mm and >2 mm) with a sensitivity of 78.00% and specificity of 89.00% and a substantial agreement (κ = 0.67; 95% CI, 0.58-0.76). We compared our results to the performance of dermatologists and dermatology residents who assessed dermoscopic and clinical images of these melanomas, and reached a sensitivity of 60.38% and specificity of 80.86% with a moderate agreement (κ = 0.41; 95% CI, 0.39-0.43). Based on our findings, this novel method may help predict the appropriate safety margins for curative melanoma excision.

Epidemiology and Treatment of Calcinosis Cutis: 13 Years of Experience.

BACKGROUND: Calcinosis cutis is a rare condition associated with different diseases, which is difficult to manage. AIMS AND OBJECTIVES: In this retrospective study, the epidemiology of calcinosis cutis and the effectiveness of various treatment regimens in its management were assessed in a single center. MATERIALS AND METHODS: The data of 34 patients suffering from calcinosis cutis (male:female = 12:22; mean age = 48.6 ± 18.6 years) treated at our department between 2003 and 2016 were analyzed retrospectively. RESULTS: Dystrophic, idiopathic, metastatic subtype, and calciphylaxis occurred in 70.6%, 11.8%, 5.9%, and 11.8% of the cases, respectively. Underlying diseases of dystrophic calcinosis included autoimmune connective tissue disease, skin trauma, cutaneous neoplasm, and inherited disorder in 58.3%, 20.8%, 12.5%, and 8.3% of the cases, respectively. Extremities were most frequently affected (n = 18). In the management, diltiazem was most frequently used in monotherapy with partial response in five of eight cases. Other drugs in monotherapy or in combination were administered in single cases. Surgical treatment resulted in least partial response in all of the cases followed (n = 7). CONCLUSION: Dystrophic was the most common subtype and autoimmune connective tissue disease was the most frequent underlying disease. We conclude that lower doses of diltiazem have only partial efficiency, and surgical therapy is at least partially effective in localized calcinosis.

Lymphomatoid Papulosis Type B in a Patient with Crohn's Disease Treated with TNF-Alpha Inhibitors Infliximab and Adalimumab.

Dear Editor, Lymphomatoid papulosis (LP) is a chronic, recurrent, usually self-limited papulonecrotic or papulonodular skin disease, which belongs to the group of primary cutaneous CD30+ lymphoproliferative disorders (1). Three main histological subtypes of LP have been recognized: type A (histiocytic), type B (mycosis fungoides-like), and type C (anaplastic large cell lymphoma-like). Recently, new histologic LP variants classified as type D (CD8-positive, cytotoxic form) and type E (angioinvasive form) have also been described. The etiology of LP has not been determined to date (2-4). Herein we report a case of LP type B evolving in a patient with Crohn's disease after treatment with infliximab and adalimumab. A 38-year-old man suffering from terminal ileitis form of luminar Crohn's disease for 10 years presented at our department. During the last 10 years, the patient had been treated with a number of conventional disease-modifying anti-inflammatory drugs including non-steroid anti-inflammatory drugs, mesalazine, and immunomodulatory agents such as corticosteroids and azathioprine. As the disease was not sufficiently controlled, TNF-α inhibitor therapy was initiated. Infliximab was administered in standard dosage (5 mg/kg body weight every 8 weeks after the induction period) for one year. Concomitant therapy with azathioprine was established to reduce the risk of adverse immunological reactions. Since the patient showed only partial clinical response, infliximab was switched to adalimumab (40 mg biweekly), resulting in notable improvement. 18 months after the initiation of adalimumab treatment, asymptomatic, small, red to brown papules developed on the extremities. Multiple lesions were observed, initially on the legs, but the symptoms rapidly progressed to the arms and trunk (Figure 1). An acquired ichthyosis further complicated the disease course by extended, extremely xerotic, scaling skin lesions. Neither systemic symptoms nor significant lymphadenopathy was observed. The clinical picture suggested either ichthyosiform mycosis fungoides or a coincidence of LP and acquired ichthyosis. The histology of a typical papule showed perivascular and periadnexal lymphoid infiltration with massive hemorrhage in the dermis. The infiltration was dense, composed of small-to-medium-sized lymphoid cells showing focal significant epidermotropism (Figure 2). Most observed epidermal lymphocytes were CD3+, CD4+, and CD30+, while the dermal infiltration had higher CD4 and lower CD30 expression (10-15%). Polymerase chain reaction (PCR) analysis of skin and peripheral blood samples did not show clonal rearrangement of T-cell receptor gamma (TcRgamma) genes. Normal phenotypes of lymphocyte subsets were detected by flow cytometry of peripheral blood. Ichthyosiform mycosis fungoides was excluded since histology of ichthyosiform skin lesions showed only hyperkeratosis with a reduced granular layer. While the cutaneous CD4+ epidermotropic infiltrate was suspicious of either mycosis fungoides or LP type B, the complexity of clinicopathological data confirmed the diagnosis of LP type B. The peripheral blood counts, serum biochemical tests, and urinalysis were within normal range, while the elevated serum anti-Saccharomyces cerevisiae antibodies (ASCA) of IgG and IgA subclasses indicated the activity of Crohn's disease. Adalimumab and azathioprine were discontinued, and oral budesonide therapy was started in combination with topical corticosteroids and PUVA phototherapy. The skin lesions resolved with hyperpigmentation, and there was no relapse during the twelve-month follow-up. Recent data suggest that LP occurs more commonly in immunocompromised patients, especially in those with solid organ or bone marrow transplants (3). Though TNF-α inhibitors have dramatically advanced the treatment of various diseases, the risk of lymphoma associated with their use remains controversial (5). Several cases of cutaneous lymphoproliferative disorders associated with TNF-α inhibitor treatment have been reported, including two patients with LP (6). One of the two patients with LP received infliximab for Crohn's disease (7), while the other one had juvenile rheumatoid arthritis and received adalimumab (8). Our case is the third report on LP developing under TNF-α inhibitor therapy and the first LP type B in a patient with Crohn's disease treated with infliximab and later with adalimumab. A further interesting aspect of our case is that it also represents an example of the known association of acquired ichthyosis with inflammatory bowel disease (9). Multidisciplinary management was needed to provide optimal care and disease outcome for our patient. Since it is usually difficult to prove causality in most of such cases, it is important to collect similar clinical observations. Acknowledgments: The authors are grateful to Dr. László Bene, Dr. József Szakonyi, and Dr. Fruzsina Kovács for additional medical care of the patient and to Tamás Szaák for the clinical photos. The authors thank Prof. Miklós Sárdy for his critical review of the paper.

Concomitant 1p36 deletion and TNFRSF14 mutations in primary cutaneous follicle center lymphoma frequently expressing high levels of EZH2 protein.

Primary cutaneous follicle center lymphoma (PCFCL) is an indolent variant of follicular lymphoma (FL) with limited information available on the genetic background of the disease. The genetic hallmark of nodal FL, the t(14;18) translocation, affecting the BCL2 gene, is rare in PCFCL. Loss of 1p36, the most common secondary chromosomal abnormality in nodal FL, has been recently reported in 16.7% of PCFCL cases. In order to further characterize PCFCL, 21 cases were analyzed using interphase fluorescence in situ hybridization with BCL2 break apart and 1p36/1q25 dual color probes. Sanger sequencing was used to investigate TNFRSF14 and EZH2 mutations and immunohistochemistry to assess BCL2, EZH2 protein expressions.1p36 deletion occurred in 22% (5/21), BCL2 gene break in 10% (2/20) of the PCFCL cases. Mutations of the candidate tumor suppressor gene of the 1p36 region, TNFRSF14 mutations were detected in 4/17 (23.5%) cases with 2 cases presenting with concurrent 1p36 deletion. EZH2 hotspot mutations at Y641, A682, and A692 were not found. High EZH2 protein expression associated with a BCL2 negative phenotype was observed in 43% (9/21) of the cases. BCL2 gene break or 1p36 deletion did not impact the prognosis; however, they showed association with advanced stages at diagnosis (p = 0.016) and a tendency with shorter event free survival (p = 0.052).In conclusion, 1p36 deletion co-occurs with acquired TNFRSF14 mutations, suggesting a role of this tumor suppressor gene in the development of a subgroup of PCFCL. High EZH2 protein expression associated with BCL2 negative phenotype is common and might represent an ideal therapeutic target.

Ex vivo nonlinear microscopy imaging of Ehlers-Danlos syndrome-affected skin.

Ehlers-Danlos syndrome (EDS) is the name for a heterogenous group of rare genetic connective tissue disorders with an overall incidence of 1 in 5000. The histological characteristics of EDS have been previously described in detail in the late 1970s and early 1980s. Since that time, the classification of EDS has undergone significant changes, yet the description of the histological features of collagen morphology in different EDS subtypes has endured the test of time. Nonlinear microscopy techniques can be utilized for non-invasive in vivo label-free imaging of the skin. Among these techniques, two-photon absorption fluorescence (TPF) microscopy can visualize endogenous fluorophores, such as elastin, while the morphology of collagen fibers can be assessed by second-harmonic generation (SHG) microscopy. In our present work, we performed TPF and SHG microscopy imaging on ex vivo skin samples of one patient with classical EDS and two patients with vascular EDS and two healthy controls. We detected irregular, loosely dispersed collagen fibers in a non-parallel arrangement in the dermis of the EDS patients, while as expected, there was no noticeable impairment in the elastin content. Based on further studies on a larger number of patients, in vivo nonlinear microscopic imaging could be utilized for the assessment of the skin status of EDS patients in the future.

Diet-induced obesity skin changes monitored by in vivo SHG and ex vivo CARS microscopy.

Obesity related metabolic syndrome and type 2 diabetes have severe consequences on our skin. Latest developments in nonlinear microscopy allow the use of noninvasive, label free imaging methods, such as second harmonic generation (SHG) and coherent anti-Stokes Raman scattering (CARS), for early diagnosis of metabolic syndrome-related skin complications by 3D imaging of the skin and the connective tissue. Our aim was to study effects of various types of diet-induced obesity in mice using these methods. We examined mice on different diets for 32 weeks. The collagen morphology was evaluated four times in vivo by SHG microscopy, and adipocytes were examined once at the end of experiment by ex vivo CARS method. A strong correlation was found between the body weight and the adipocyte size, while we found that the SHG intensity of dermal collagen reduces considerably with increasing body weight. Obese mice on high-fat diet showed worse results than those on high-fat - high-fructose diet. Animals on high-fructose diet did not gain more weight than those on ordinary diet despite of the increased calorie intake, but their collagen damage was nonetheless significant. Obesity and high sugar intake damages the skin, mainly the dermal connective tissue and subcutaneous adipose tissue, which efficiently can be monitored by in vivo SHG and ex vivo CARS microscopy.

Histopathological aspects and differential diagnosis of CD8 positive lymphomatoid papulosis.

Lymphomatoid papulosis (LyP) belongs to CD30+ lymphoproliferative disorders with indolent clinical course. Classic histological subtypes, A, B and C are characterized by the CD4+ phenotype, while CD8+ variants, most commonly classified as type D, were reported in recent years. We present 14 cases of CD8+ LyP. In all patients, self-resolving or treatment-sensitive papules were observed. Of 14 cases 7 produced results with typical microscopic features of LyP type D mimicking primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. The infiltration pattern in 4 of 14 cases were consistent with classic LyP type B, without CD30 expression in two cases, resembling mycosis fungoides (MF). The morphology of 2 of 14 cases shared a certain consistency with classic type A and C, lacking eosinophils and neutrophils. Extensive folliculotropism characteristic to type F was observed in 1 of 14 case. Significant MUM1 and PD1 expression were detected in 2 of 14 and 3 of 14 cases, respectively. We concluded that CD8+ LyP may present with different histopathological features compared with type D, similar to CD4+ LyP variants. Differential diagnoses include CD8+ papular MF, folliculotropic MF and anaplastic large cell lymphoma in addition to primary cutaneous aggressive epidermotropic T-cell lymphoma. We emphasise that rare CD8+ LyP cases may exist with CD30-negativity.