Primary localized cutaneous lichen myxedematosus with light chain-restricted plasma cells: A distinct variant of the localized form of lichen myxedematosus.

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.

DUSP22-IRF4 Rearranged CD30-Positive Primary Cutaneous Lymphoproliferative Disorder With Gamma/Delta Phenotype.

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.

Spindle Cell Lipoma With Florid Primary Follicular Lymphocytic Hyperplasia: A Novel Association With Potential Diagnostic Pitfalls.

ABSTRACT: Spindle cell lipoma (SCL) is a benign subcutaneous lipomatous neoplasm with a heterogeneous histologic appearance that varies greatly depending on the amount of fat, collagen, and myxoid stroma, which define the multiple subtypes of SCL, such as fat poor SCL, pseudoangiomatous SCL, and dendritic fibromyxolipoma. Cutaneous lymphoid hyperplasia is a spectrum of benign conditions characterized by reactive B-cell and T-cell cutaneous lymphocytic infiltrates. Cutaneous B-cell lymphoid hyperplasia is a heterogeneous group of non-neoplastic conditions that can be observed as reactive phenomena to infections, medications, allergens, or neoplasms and must be distinguished from cutaneous B-cell lymphomas. Here, we report a novel case of spindle cell lipoma, associated with B-cell primary lymphoid follicular hyperplasia, mixed within the tumor in a peculiar pattern, while discussing potential diagnostic pitfalls with low-grade B-cell lymphomas. This is the first report of such association in the literature.

Lichen Planopilaris Pemphigoides: A Novel Bullous Dermatosis Due to Programmed Cell Death Protein-1 Inhibitor Therapy.

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.

Overlapping Features of Primary Cutaneous Marginal Zone Lymphoproliferative Disorder and Primary Cutaneous CD4 + Small/Medium T-Cell Lymphoproliferative Disorder : A Diagnostic Challenge Examined by Genomic Analysis.

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.

Localized Lichen Myxedematosus With Plasma Cell Light Chain Restriction: Is It the Exception or the Rule?

Lichen myxedematosus is a chronic cutaneous mucinosis that can present on a spectrum from localized cutaneous lesions to systemic disease of scleromyxedema. The clinical presentation of localized cutaneous lichen myxedematosus is waxy lichenoid papules, nodules, and/or plaques that have histopathologic findings of mucin deposition and a variable degree of fibroblast proliferation. There is an absence of serum paraproteins, and there are no other systemic causes of cutaneous mucinosis such as thyroid disease. The pathogenesis of lichen myxedematosus is unknown. We report 3 cases of localized cutaneous lichen myxedematosus with a light chain-restricted plasmacytic component by in situ hybridization. Our findings deliver an insight for disease pathogenesis and highlight for the first time, the significance of plasma cells in lesions of localized cutaneous lichen myxedematosus. We suggest that plasma cell light chain restriction could represent a clue to distinguish localized cutaneous disease from systemic disease.

A case of leprosy in central Florida.

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.

Die histologischen Typen der lymphomatoiden Papulose - Ein Vorschlag für die Vereinfachung des Buchstabenchaos.

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.

Lymphomatoid papulosis - making sense of the alphabet soup: a proposal to simplify terminology.

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.

Immunocytochemical p63 expression discriminates between primary cutaneous follicle centre cell and diffuse large B cell lymphoma-leg type, and is of the TAp63 isoform.

AIMS: The p63 gene shares structural and functional homologies with the p53 family of transcriptional activators, but differs in exhibiting a consistent expression pattern in normal tissues. Although p63 is rarely mutated in malignancy studies of primary human tumours and cell lines suggest that p63 may promote tumour development. In non-Hodgkin's nodal lymphoma, TAp63 expression in follicular lymphoma (54%) and diffuse large B cell lymphoma (34%) has been described and correlated with the proliferative index. In this study, we analysed a series of primary cutaneous B cell lymphomas for immunohistochemical expression of p63. METHODS AND RESULTS: Thirty cases of diffuse large B cell lymphoma leg type (pcDLBCLL) and 34 cases of follicle centre cell lymphoma (pcFCCL) were stained using a generic antibody to p63, and a subset of these with an antibody specific for delta-Np63 isoform. The results indicate a significant difference between pcDLBCLL (21 of 30) and pcFCCL (four of 34) in p63 expression (P = 0.000); expression correlated strongly with the proliferation rate as assessed by Ki-67 (P = 0.015). None of the p63((+)) cases tested expressed the delta-Np63 isoform, suggesting that expression is of the TAp63 isoform. CONCLUSIONS: Functional studies are required to clarify the significance of p63 overexpression in primary cutaneous B cell lymphoma.

Langerhans cell sarcoma with lineage infidelity/plasticity: a diagnostic challenge and insight into the pathobiology of the disease.

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.

Defining early mycosis fungoides: validation of a diagnostic algorithm proposed by the International Society for Cutaneous Lymphomas.

BACKGROUND: Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma and is often difficult to diagnose. Early-stage disease is particularly challenging and requires clinical and histopathologic correlation to make an accurate diagnosis. In order to facilitate the diagnosis of early MF, an algorithm has been proposed by the International Society for Cutaneous Lymphomas (ISCL) whereby clinical and histopathologic characteristics as well as immunohistochemistry and T-cell receptor gene rearrangement studies may be applied to suspected cases of MF. The diagnostic utility of this algorithm has not yet been validated. We sought to determine the validity of the proposed algorithm via an investigator-blinded, retrospective, case-control study. METHODS: A total of 34 cases were randomly selected from the database of a clinic for cutaneous T-cell lymphomas and included patients with MF and patients with clinicopathologic mimics. The proposed diagnostic algorithm was systematically applied to the entire cohort. Each case was assigned a composite score based on the parameters in the proposed algorithm. RESULTS: Among the 24 cases of MF, 21 cases achieved four or more points through application of the algorithm. Among the 10 cases of MF mimics, only four achieved four or more points. This difference was significant (Fisher's exact test, p = 0.009). The sensitivity of the 4-point threshold for a diagnosis of MF was 87.5% and the specificity was 60%. CONCLUSIONS: The diagnostic algorithm proposed by the ISCL is a statistically valid method for defining cases of early MF and distinguishing these cases from other benign dermatoses. However, the clinical utility of the algorithm may be limited by its low specificity. Further refinement of the algorithm may improve its accuracy.

Chromosomal rearrangements of 6p25.3 define a new subtype of lymphomatoid papulosis.

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.

Pain associated with aminolevulinic acid-photodynamic therapy of skin disease.

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.

Reactivation of DNA viruses in association with histone deacetylase inhibitor therapy: a case series report.

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.

Recent advances in T-cell regulation relevant to inflammatory dermatopathology.

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.

JAAD Grand Rounds quiz. Asymptomatic necrotic ulcer on leg.

LEARNING OBJECTIVES: At the conclusion of this learning activity, physician participants should be able to assess their own diagnostic and patient management skills and use the results of this exercise to help determine personal learning needs that can be addressed through subsequent CME involvement. Instructions for claiming CME credit appear in the front advertising section. See last page of Contents for page number. Instructions: In answering each question, refer to the specific directions provided. Because it is often necessary to provide information occurring later in a series that give away answers to earlier questions, please answer the questions in each series in sequence.

Conservation of genetic alterations in recurrent melanoma supports the melanoma stem cell hypothesis.

It is generally accepted that human cancers derive from a mutated single cell. However, the genetic steps characterizing various stages of progression remain unclear. Studying a unique case of metastatic melanoma, we observed that cell lines derived from metachronous metastases arising over a decade retained a central core of genetic stability in spite of divergent phenotypes. In the present study, we expanded our previous observations comparing these autologous cell lines of clonal derivation with allogeneic ones and correlated array comparative genomic hybridization (aCGH) with gene expression profiling to determine their relative contribution to the dynamics of disease progression. aCGH and gene expression profiling were performed on autologous cell lines and allogeneic melanoma cell lines originating from other patients. A striking correlation existed between total extent of genetic imbalances, global transcriptional patterns, and cellular phenotypes. They did not follow a strict temporal progression but stemmed independently at various time points from a central core of genetic stability best explained according to the cancer stem cell hypothesis. Although their contribution was intertwined, genomic imbalances detectable by aCGH contributed only 25% of the transcriptional traits determining autologous tumor distinctiveness. Our study provides important insights about the dynamics of cancer progression and supports the development of targeted anticancer therapies aimed against stable genetic factors that are maintained throughout the end stage of disease.