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Abstract: Indeterminate dendritic cell histiocytosis (IDCH) is a rare and poorly understood entity characterized by accumulation of CD1a+/S100+ histiocytes (as Langerhans cell histiocytosis [LCH]) but with reduced-absent expression of Langerin/CD207. We assembled 43 cases of IDCH (defined by CD1a+/CD207<20% immunophenotypic profile) examining the clinical, pathologic, and molecular landscape. Median age at presentation was 70 years (interquartile range, 44-80) with cutaneous (31/43; 72%) and nodal (11/43; 26%) involvement predominating. Eighteen (42%) individuals had an associated nonhistiocytic hematopoietic neoplasm ("secondary" IDCH) whereas 7 of 43 (16%) had a concurrent non-IDCH histiocytosis ("mixed" histiocytosis). Most cases exhibited morphology indistinguishable from LCH but with a CD1c+/CSF1R(CD115)- phenotype, mirroring the signature of normal indeterminate cells and conventional DC type 2. Mutational analysis revealed frequent KRAS (13/32; 41%) and BRAF p.V600E (11/36, 31%) mutations that were nearly mutually exclusive. RNA-sequencing analysis uncovered ETV3::NCOA2 fusion in 6 other patients presenting as a sole genetic alteration without any other concurrent histiocytic or hematopoietic neoplasm. BRAF and MAP2K1 alterations were significantly associated with partial/retained (1%-20%) Langerin expression (P = .005) and mixed histiocytosis (P = .002). Remarkably, myeloid alterations (DNMT3A, TET2, and SRSF2) co-occurred in IDCH tissues of several individuals. Paired sequencing of IDCH and concurrent non-IDCH hematopoietic neoplasm in 4 individuals revealed shared mutations. Age at diagnosis and any nodal involvement at diagnosis predicted inferior overall survival, but BRAF/RAS pathway alterations did not affect outcome. These data have implications for the diagnostic evaluation, classification, and therapeutic management of IDCH., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Lichen myxedematosus (LM) is a chronic cutaneous mucinosis that can present as a localized skin lesion or as a generalized systemic disease termed scleromyxedema. The differential diagnosis is determined by a combination of clinical presentation, serological studies, and histopathological examination. Currently, well-established and accepted histopathological features to distinguish localized LM from scleromyxedema have not been elucidated. Our recent publication, together with a retrospective literature review, suggests that the presence of groups of light chain-restricted plasma cells represents a distinct histopathological clue for the diagnosis of localized LM. In this report, we provide two additional cases of localized LM with lambda light chain-restricted plasma cells, together with clinical and histopathological findings that are similar to our previous publication. These cases support our theory that the light chain-restricted plasmacytic microenvironment is primarily attributed to the pathogenesis of localized LM. Therefore, we consider these cases to constitute a clinically and pathologically new variant of localized LM and name it primary localized cutaneous LM with light chain-restricted plasma cells., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Abstract: CD30-positive primary cutaneous lymphoproliferative disorders (CD30 + PCLPD) are a heterogeneous group of cutaneous T-cell lymphoma (CTCL) that includes lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma. They exist as a clinical and pathological spectrum, which display significant overlap and variability. The diagnosis is made based on correlation between clinical and histopathologic findings. LyP with 6p25.3 rearrangement subtype represents <5% of LyP cases and is defined by DUSP22-IRF4 rearrangement on 6p25.3 locus. The reported cases express the alpha/beta T-cell receptor and follow an indolent clinical behavior typical of LyP. The same rearrangement is detected in 28% of anaplastic large cell lymphoma. We hereby present an extraordinary case of CD30 + PCLPD with DUSP22-IRF4 rearrangement and novel expression of gamma/delta T-cell immunophenotype in a young patient. Although the gamma/delta T-cell immunophenotype has been described in many other T-cell lymphomas, this is the first reported association with CD30 + PCLPD with DUSP22-IRF4 rearrangement., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Lichen planus pemphigoides (LPPemph), apart from bullous pemphigoid, is a rare bullous dermatosis that can be induced by programmed cell death protein-1 (PD-1)/PD ligand 1 (PD-L1) inhibitors. The primary location of PD-1/PD-L1 inhibitor-induced LPPemph has previously only been reported at the nonfollicular dermal-epidermal junction. We present a case of nivolumab-induced LPPemph with an intense perifollicular lichenoid reaction, prominent multifocal perifollicular clefting, which in addition, was also accompanied by linear IgG and C3 immunofluorescence deposits along the dermal-epidermal junction as well as demonstrating a perifollicular pattern. Intriguingly, the serological study of BP180 and BP230 antibodies was negative, suggesting the presence of additional novel antibodies, which primarily favor hair follicles and may contribute to the pathogenesis. Therefore, we consider this entity a novel variant of PD-1/PD-L1 inhibitor-induced bullous dermatosis. To the best of our knowledge, this is the first report that highlights perifollicular bullae accompanied by immunofluorescence findings in a PD-1/PD-L1 inhibitor-induced lesion. We propose a new immunotherapy associated entity, lichen planopilaris pemphigoides, and emphasize the significance of perifollicular changes in the pathogenesis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Primary cutaneous marginal zone lymphoproliferative disorder (PCMZL) and primary cutaneous CD4 + small/medium T-cell lymphoproliferative disorder (CD4 + TLPD) are indolent lymphoproliferative disorders. However, cases with overlapping features can be challenging. We identified 56 CD4 + TLPD and 38 PCMZL cases from our pathology archives. Clinical, morphologic, and immunophenotypic features were reviewed. Polymerase chain reaction for immunoglobulin (IG) and T-cell receptor gamma (TRG) gene rearrangements were analyzed. Next-generation sequencing studies were performed on 26 cases with adequate material, 19 with CD4 + TLPD, and 7 with PCMZL. CD4 + TLPD presented mostly (91%) as solitary lesions, located in the head and neck area (64%), while PCMZL occurred mostly in the upper extremity (47%) and trunk (34%). Lesions were sometimes multiple (40%) and recurrences (67%) were more common. Cases of PCMZL had an increase in reactive CD3 + T cells, with frequent programmed cell death protein 1 expression, whereas cases of CD4 + TLPD often contained abundant reactive B cells. Twenty-five cases were identified as having overlapping features: 6 cases of PCMZL were clonal for both IG and TRG; 11 cases of CD4 + TLPD were clonal for IG and TRG and 6 cases of CD4 + TLPD had light chain-restricted plasma cells. By next-generation sequencing, 23 variants were detected in 15 genes, with PCMZL more likely to show alterations, most commonly affecting TNFAIP3 and FAS, altered in 5 cases. Both entities have an indolent clinical course with response to conservative therapy and management, and warrant interpretation as a lymphoproliferative disorder rather than overt lymphoma., Competing Interests: Conflicts of Interest and Source of Funding: Supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Hansen disease, also known as leprosy, is a chronic granulomatous infectious disease that is caused by Mycobacterium leprae . We report an unusual case of a 65-year-old man who presented with multiple anesthetic, annular, erythematous, scaly plaques with a raised border without any known exposures to leprosy. Histologic examination revealed a perineural lymphohistiocytic infiltrate and rare bacilli demonstrated on Fite staining. After confirmation with polymerase chain reaction (PCR) and consultation with the National Hansen's Disease Program (Baton Rouge, Louisiana), the patient was placed on a regimen of rifampicin 600 mg once monthly and dapsone 100 mg once daily for 6 months, which showed considerable improvement. This case demonstrates the identification of leprosy in central Florida, a region that is not known to be endemic to the disease. Leprosy, however rare, must be part of a practitioner's differential diagnosis even without history of traditional exposures.

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.)

Die lymphomatoide Papulose (LYP) ist klinisch durch rezidivierende papulonoduläre Läsionen charakterisiert. Im Gegensatz zu dieser stereotypen klinischen Präsentation zeigt die Erkrankung ein breites histologisches Spektrum mit verschiedenen Infiltratmustern, unterschiedlichen Tumorzellgrößen und variablen Phänotypen. Die revidierte WHO-Klassifikation 2016 umfasst die histologischen LYP-Typen A bis E und einen sechsten Typ, dem eine spezielle Mutation zugrunde liegt. Darüber hinaus werden jedoch immer wieder neue Typen vorgeschlagen, wobei sich die Ausweitung nicht ausschließlich auf histologische Muster bezieht, sondern sich auch auf klinische und genetische Aspekte ausdehnt. Dies führt zu einer Ausweitung der alphabetischen Liste mit zunehmender Komplexität der Terminologie und kann anstelle eines vereinfachten diagnostischen Zugangs zur Verwirrung führen. Zudem kann es zu Überschneidungen unterschiedlicher Typen kommen. Diese Entwicklung wirft die Frage auf, wie die Terminologie der lymphomatoiden Papulose vereinfacht werden kann, ohne dabei auf die histologischen Besonderheiten zu verzichten. Wir schlagen daher einen praktischen Zugang zur Terminologie der lymphomatoide Papulosen vor, welcher sich ausschließlich auf deskriptive Begriffe beschränkt und nicht auf einer alphabetischen Bezeichnung der LYP-Typen beruht. Unser Vorschlag soll einen praktikablen und benutzerfreundlichen Zugang zur Terminologie der lymphomatoiden Papulose ermöglichen und damit den diagnostischen Prozess sowie die Kommunikation zwischen Klinikern und Pathologen vereinfachen., (© 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Langerhans cell sarcoma is a very rare and aggressive tumor of Langerhans cell lineage, for which aberrant expression of T-cell-related antigens has not yet been reported in a primary skin tumor. The authors describe the first known case of a primary cutaneous Langerhans cell sarcoma with lineage infidelity and use comparative genomic hybridization to investigate the genetic composition of the tumor and detect DNA copy number alterations throughout its entire genome. The case involves a 62-year-old woman who presented with an irregular nodule on the forehead surrounded by smaller lesions in its vicinity. The clinical impression was melanoma with satellitosis. The biopsy specimen showed an epidermotropic tumor with moderate-to-marked cellular pleomorphism and significantly increased mitotic rate but no necrosis. The immunoprofile of the lesion was remarkable, as next to common Langerhans cell markers: Langerin, CD1a, S100, and CD4; it also exhibited an aberrant T-cell phenotype with the expression of CD2, CD3, and CD43. In addition, fascin and CD30 were also expressed, further exaggerating potential diagnostic pitfalls. Langerhans cell lineage was confirmed by the demonstration of characteristic Birbeck granules on electron microscopy. Whole genome analysis for copy number changes and loss of heterozygosity showed a complex karyotype with variable hyperdiploidy and numerous allelic imbalances. Significant findings included a homozygous deletion at 9p21 involving the CDKN2A and loss of heterozygosity at 17p involving TP53 gene, coupled with a TP53 missense mutation. Despite reexcision and multiagent systemic chemotherapy, the patient died of metastasis 2 years after diagnosis. This case is an outstanding example of lineage infidelity in a hematologic malignancy and the utilization of comparative genomic hybridization in characterizing its genetic abnormalities.

Lymphomatoid papulosis (LyP) is an indolent cutaneous lymphoproliferative disorder with clinical and pathologic features overlapping those of both reactive conditions and aggressive lymphomas. Recurrent genetic abnormalities in LyP have not been previously identified. Here, we describe the clinical, immunophenotypic, and genetic characteristics of cutaneous lymphoproliferative lesions showing distinctive and previously undescribed histologic features in 11 patients. All patients were older adults (67 to 88 y) with predominantly localized lesions and clinical presentations suggesting benign inflammatory dermatoses or low-grade epithelial tumors. Histologically, lesions showed a biphasic growth pattern, with small cerebriform lymphocytes in the epidermis and larger transformed lymphocytes in the dermis. All had a T-cell immunophenotype. The pathologic features raised the possibility of an aggressive T-cell lymphoma such as transformed mycosis fungoides. However, no patient developed disseminated skin disease or extracutaneous spread. Untreated lesions regressed spontaneously. All cases harbored chromosomal rearrangements of the DUSP22-IRF4 locus on 6p25.3. The overall findings suggest that these cases represent a newly recognized LyP subtype characterized by 6p25.3 rearrangements. The benign clinical course in all 11 patients despite pathologic features mimicking an aggressive lymphoma emphasizes the importance of clinicopathologic correlation, incorporating molecular genetic analysis when possible, during the evaluation of cutaneous lymphoproliferative disorders.

Background: Pain during topical aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) limits the use of this treatment of skin diseases., Objective: We sought to summarize the effectiveness of interventions to reduce ALA-PDT-related pain, and to explore factors contributing to pain induction., Methods: A PubMed search was performed to identify all clinical PDT trials (2000-2008) that used ALA or methyl-ALA, enrolled at least 10 patients per trial, and used a semiquantitative pain scale., Results: In all, 43 articles were identified for review. Pain intensity is associated with lesion size and location and can be severe for certain diagnoses, such as plaque-type psoriasis. Results are inconsistent for the correlation of pain with light source, wavelength of light, fluence rate, and total light dose. Cooling represents the best topical intervention., Limitations: Pain perception differs widely between patients and can contribute to variability in the reported results., Conclusion: Gamma-aminobutyric acid receptors, cold/menthol receptors (transient receptor potential cation channel, subfamily M, member 8), and vanilloid/capsaicin receptors (transient receptor potential cation channel, subfamily V, member 1) may be involved in pain perception during ALA-PDT and are therefore worthy of further investigation.

Elephantiasis nostras verrucosa (ENV) is an unusual skin condition characterized by dermal fibrosis and hyperkeratotic verrucous lesions resulting from chronic nonfilarial lymphoedema. The condition is similar to 'elephantiasis tropica', in which elephantiasis develops secondary to filariasis. Lymphatic obstruction can be primary or due to various causes such as surgery, tumour, radiation, congestive heart failure or obesity. Recurrent attacks of cellulitis lead to further impairment of lymphatic drainage, causing permanent swelling, dermal fibrosis and epidermal thickening. We report a case of a 56-year-old man with systemic sclerosis (SS), who presented with painful lesions on both legs, consistent with ENV. He developed extensive, fungating, papillomatous lesions on the skin of the legs, toes and dorsa of the feet over a period of 3 years. Histology revealed dense dermal fibrosis, oedema of the papillary dermis and extensive pseudo-epitheliomatous changes. To our knowledge, this is the first report of ENV in which SS was considered to be the primary cause for the impairment of lymphatic flow.

Histone deacetylase inhibitors are a class of anti-neoplastic agents that induce growth arrest, differentiation, and/or apoptotic cell death of transformed cells in vitro and in vivo. A phase II study exploring the efficacy of romidepsin, an histone deacetylase inhibitor, in patients with cutaneous or peripheral T-cell lymphomas was initiated at the National Cancer Institute. To date, over 120 patients with T-cell lymphoma have been treated on a multi-institutional phase II trial of romidepsin. Reactivation of latent DNA viruses including EBV, HBV, and VZV is well described as a consequence of the immune suppression associated with systemic chemotherapy. The incidence of viral reactivation in patients treated with histone deacetylase inhibitors is not yet known. We report the observation of EBV-associated illnesses in 2 patients and the reactivation of HBV in an additional patient treated with romidepsin. These cases may represent reactivation of DNA viruses due to histone deacetylase inhibitor induced immunosuppression, or direct promotion of viral replication via histone deacetylase inhibitor induced chromatin remodeling, or, alternatively, may be related to the underlying disease process. These observations suggest that vigilance for DNA virus reactivation is needed to quantify the risk in patients treated with histone deacetylase inhibitors.

Inflammatory dermatoses encompass an enormous area of dermatopathology. Our understanding of the subject comes from combination of histopathological observations and relevant clinical information. Diagnoses are generally reached at the hematoxylin and eosin (H&E) level by using various pattern recognition approaches including one devised by Dr Ackerman et al. Recent advances in cell biology and immunology especially the field of T-cell regulation shed light to the intricate cellular interactions, associations and connect to inflammatory dermatopathology. This review attempts to identify and put into context the most significant advances in cellular biology relevant to the topic. Most of the information presented here is not necessarily relevant to our regular work at the moment; however, the new information will surely channel into our practice to provide a better, more accurate, semi-individualized diagnostic approach in the not too far future., ((c) 2009 John Wiley & Sons A/S.)

Resiniferatoxin (RTX) is an ultrapotent capsaicin analog that binds to the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1). There is a large body of evidence supporting a role for TRPV1 in noxious-mediated and inflammatory hyperalgesic responses. In this study, we evaluated low, graded, doses of perineural RTX as a method for regional pain control. We hypothesized that this approach can provide long-term, but reversible, blockade of a portion of nociceptive afferent fibers within peripheral nerves when given at a site remote from the neuronal perikarya in the dorsal root ganglia. Following perineural RTX application to the sciatic nerve, we demonstrated a significant inhibition of inflammatory nociception that was dose- and time-dependent. At the same time, treated animals maintained normal proprioceptive sensations and motor control, and other nociceptive responses were largely unaffected. Using a range of mechanical and thermal algesic tests, we found that the most sensitive measure following perineural RTX administration was inhibition of inflammatory hyperalgesia. Recovery studies showed that physiologic sensory function could return as early as two weeks post-RTX treatment, however, immunohistochemical examination of the DRG revealed a partial, but significant reduction in the number of the TRPV1-positive neurons. We propose that this method could represent a beneficial treatment for a range of chronic pain problems, including neuropathic and inflammatory pain not responding to other therapies.