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Background: Folliculotropic mycosis fungoides (FMF) is a rare cutaneous malignancy that can be mistaken for inflammatory diseases, such as discoid lupus erythematosus (DLE), due to the variability of histopathological findings., Methods: This study aims to provide dermatopathologists with evidence-based histopathologic criteria to distinguish DLE from FMF by reporting overlapping and distinguishing microscopic features. Forty-three biopsies from patients with a confirmed diagnosis of DLE or FMF were graded for the presence or absence of 18 histopathologic features., Results: The main histopathologic findings present in nearly all DLE and FMF biopsies were folliculocentric and folliculotropic patterns. Comedones, granulomas, and folliculitis were not prominent. Follicular hyperplasia, follicular plugging, interstitial mucin, lichenoid/interface dermatitis, and plasma cells were significantly more common in DLE biopsies, while follicular mucinosis and eosinophils were significantly more common in FMF samples. Cytologic atypia ranged from none to mild in DLE and mild to moderate in FMF. Rarely, both sets of biopsies contained epidermotropism, spongiosis, or peri-eccrine infiltration., Conclusion: While many histopathological features present in DLE overlap with features found in FMF, such as folliculocentrism and folliculotropism, significant differences do exist. Therefore, when diagnosing FMF, it is important to follow established criteria that differentiate this malignancy from inflammatory conditions such as DLE., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The diagnosis of cutaneous T-cell lymphoma (CTCL) remains challenging. Demonstration of a clonal T-cell population using T-cell receptor (TCR) gene rearrangement studies by next-generation sequencing (NGS) has been explored in several studies. This review summarizes the current literature on NGS-based sequencing methods for the assessment of TCR clonality in the evaluation of atypical cutaneous lymphoid infiltrates and CTCL on behalf of the American Society of Dermatopathology Appropriate Use Criteria Committee (lymphoproliferative subgroup). PubMed was searched for relevant articles, including CTCL and NGS, for clonality from 1967 to 2022. Thirteen studies were included in the analysis. The skin was the most commonly assayed compartment with TCR NGS. Sensitivity for TCR NGS in the skin ranged between 69% and 100%, compared to 44%-72% for polymerase chain reaction (PCR)-capillary electrophoresis. Specificity for TCR NGS in the skin ranged from 86% to 100%, compared to 77%-88% for PCR capillary electrophoresis. TCR NGS was also reported to have potential prognostic value in CTCL and can also be used to detect relapse and/or minimal residual disease after treatment., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Appropriate use criteria (AUC) provide patient-centered physician guidance in test selection. An initial set of AUC was reported by the American Society of Dermatopathology (ASDP) in 2018. AUC reflect evidence collected at single timepoints and may be affected by evolving evidence and experience. The objective of this study was to update and expand AUC for selected tests., Methods: RAND/UCLA (RAND Corporation [Santa Monica, CA]/University of California Los Angeles) methodology used includes the following: (a) literature review; (b) review of previously rated tests and previously employed clinical scenarios; (c) selection of previously rated tests for new ratings; (d) development of new clinical scenarios; (e) selection of additional tests; (f) three rating rounds with feedback and group discussion after rounds 1 and 2., Results: For 220 clinical scenarios comprising lymphoproliferative (light chain clonality), melanocytic (comparative genomic hybridization, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, telomerase reverse transcriptase promoter), vascular disorders (MYC), and inflammatory dermatoses (periodic acid-Schiff, Gömöri methenamine silver), consensus by panel raters was reached in 172 of 220 (78%) scenarios, with 103 of 148 (70%) rated "usually appropriate" or "rarely appropriate" and 45 of 148 (30%), "appropriateness uncertain.", Limitations: The study design only measures appropriateness. Cost, availability, test comparison, and additional clinical considerations are not measured. The possibility that the findings of this study may be influenced by the inherent biases of the dermatopathologists involved in the study cannot be excluded., Conclusions: AUC are reported for selected diagnostic tests in clinical scenarios that occur in dermatopathology practice. Adhering to AUC may reduce inappropriate test utilization and improve healthcare delivery., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Atypical cutaneous lymphoid infiltrates are challenging lesions in dermatopathology. We present a summary of the literature regarding kappa and lambda immunohistochemistry (IHC) and in situ hybridization (ISH) in the evaluation of atypical cutaneous or mucosal lymphoid infiltrates., Methods: Relevant articles from 1967 to 2018 in the English language were identified and summarized. In the absence of larger studies, case series of n ≥ 3 were included., Results: Sixty-three articles assessing kappa and lambda IHC and/or ISH were identified. Most focused on marginal zone lymphomas. Other lymphomas included follicle center lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, lymphoplasmacytic lymphoma, plasmablastic lymphoma, multiple myeloma, monoclonal gammopathy of undetermined significance, and polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS). Non-neoplastic lesions included reactive lymphoid hyperplasia, cutaneous plasmacytosis, connective tissue disease, IgG4-related disease, acrodermatitis chronic atrophicans, Zoon balanitis, dermatitides, and infiltrates around epithelial dysplasias/neoplasias., Conclusion: Kappa and lambda IHC and ISH are useful tools in the evaluation of cutaneous B-cell lymphomas and plasma cell neoplasms. The literature supports that the detection of light-chain restriction by IHC and ISH is one of the most useful findings in the differential diagnosis of reactive lymphoid hyperplasia vs B-cell lymphoma with plasmacytic differentiation., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Cutaneous lymphoproliferative disorders remain a challenging aspect of dermatopathology, in part due to the rarity of the entities and extreme variability in clinical outcomes. Although many of the entities remain unchanged, the approach to some of them has changed in the new 2016 classification scheme of the World Health Organization. Chief among these are Epstein-Barr virus-associated lymphoproliferative disorders such as Epstein-Barr virus-associated mucocutaneous ulcer and hydroa vacciniforme-like lymphoproliferative disorder, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, primary cutaneous acral CD8+ T-cell lymphoma, primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, and breast implant-associated anaplastic large cell lymphoma. In addition, translocations and gene rearrangements such as those involving the 6p25.3 locus have started to inform diagnosis and classification of anaplastic large cell lymphoma and lymphomatoid papulosis. In this review, we will examine what is new in the diagnostic toolbox of cutaneous lymphoproliferative disorders.

Background: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy, and physician decision-making., Objectives: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology., Methods: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience, and expert judgment, was used to develop AUC in dermatopathology., Results: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate" and 52 (25%) "rarely appropriate" and 43 (20%) having "uncertain appropriateness.", Limitations: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost., Conclusions: The ultimate decision to order specific tests rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-the AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Despite the efficacy of BRAF-targeted and PD-L1-related immune therapies in tackling metastatic melanoma, a significant number of patients exhibit resistance. Given this, the objective of the current study was to ascertain concordance of somatic mutations in BRAF/NRAS/TERT and immunohistochemical PD-L1 and CD8 in matched primary cutaneous and metastatic melanoma. A total of 43 archival paired samples with sufficient material for genetic and immunohistochemical analyses met the criteria for inclusion in the study. Immunohistochemistry was performed for PD-L1 and CD8 and direct-DNA Sanger sequencing for BRAF/NRAS/TERT promoter mutational analyses. Agreement between paired samples was assessed using Cohen κ. Poor concordance among primary and corresponding metastases was noted in BRAF (9/42 cases discordant, κ = 0.49; 95% confidence interval [CI], 0.21-0.77; P = .0013), TERT promoter mutations (13/41 cases discordant, κ = 0.33; 95% CI, 0.04-0.62; P = .033), tumoral PD-L1 immunoexpression (9/43 cases discordant, κ = 0.39; 95% CI, 0.07-0.72; P = .0099), and immunoexpression of CD8 + T lymphocytes (12/43 cases discordant, κ = 0.44; 95% CI, 0.19-0.69; P = .002). Although NRAS1 and NRAS2 were highly concordant (42/43 and 39/43 cases, respectively), discordant NRAS2 mutational status was associated with a median time to metastasis of 90 versus 455 days for pairs with concordant status (P = .07). Although limited by sample size, our findings suggest that consideration be given to mutational analysis of metastatic tissue rather than the primary to guide BRAF-targeted therapy and question the roles of TERT promoter mutations and PD-L1 as predictive biomarkers in malignant melanoma., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy and physician decision-making., Objectives: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology., Methods: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience and expert judgment, was used to develop AUC in dermatopathology., Results: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate," 52 (25%) "rarely appropriate" and 43 (20%) "uncertain appropriateness.", Limitations: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost., Conclusions: The ultimate decision of when to order specific test rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared.

Background: Appropriate use criteria have been developed for many tests using expert judgment, evidence-based practice and clinical experience. In this context, we report the opinions of practitioners about clonality assays in various clinical scenarios where cutaneous lymphoma is suspected., Methods: An Appropriate Use Criteria Task Force sponsored by the American Society of Dermatopathology (ASDP) synthesized clinical scenarios for cutaneous lymphoproliferative disorders (LPDs). We conducted, summarized and presented a relevant literature search to an audience of 144 dermatopathologists with a variety of practice experiences at the 53rd Annual Meeting of the ASDP in Chicago, IL., Results: Twenty-seven clinical scenarios for LPDs (13 T-cell and 14 B-cell) were defined. Forty relevant studies for T-cell receptor gene clonality assays and 20 relevant studies for IgH/IgK clonality assays were identified. Audience response data from participating dermatopathologists reflected a wide variety of approaches to the application of clonality assays in the evaluation of LPDs, based on practice setting, personal experience and test availability., Conclusions: Our clinical scenario analysis and literature review revealed well-supported clinical scenarios and identified opportunities for additional research to further define the utility of clonality assays in some clinical scenarios., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Knowledge of staining pattern of certain immunostains might be useful in the classification of cutaneous adnexal tumors that can have clinical importance. We studied GATA3 and MYB expression in archival materials of 220 adnexal tumors comprised of sebaceous carcinomas, follicular tumors, apocrine carcinoma, predominantly apocrine tumors, predominantly eccrine tumors, and others including adenoid cystic carcinomas. Nuclear GATA3 expression was seen in 70% (153/220) of cases, including sebaceous carcinoma (93%), apocrine carcinoma (93%), follicular neoplasms (100%), and predominantly apocrine neoplasms (69%), yet only 38% of predominantly eccrine neoplasms. Nuclear MYB expression was seen in 43% (81/188) of cases, including adenoid cystic carcinoma (90%), predominantly apocrine tumors (66%), follicular neoplasms (49%), apocrine carcinomas (14%), predominantly eccrine tumors (11%), and sebaceous carcinomas (4%). GATA3 and MYB expression were noted in 43% (9/21) and 24% (5/21) of cutaneous metastases, respectively. Expression of both GATA3 and MYB was noted in 33% (60/184) of primary adnexal tumors versus 19% (4/21) of cutaneous metastases. GATA3 preferentially labels tumors with follicular, sebaceous, and apocrine differentiation. MYB is potentially a helpful stain in the distinction of desmoplastic trichoepithelioma versus basal cell carcinoma. The coexpression of GATA3 and MYB might be helpful in the distinction of primary cutaneous adnexal carcinoma versus metastatic breast, salivary gland, or urothelial carcinoma.

Objective: We report a truly quantitative technology for PD-L1 expression in non-small cell lung cancer (NSCLC). In addition, we present a non-enzymatic technology that creates a cell suspension from fresh tumor tissue so that either fine-needle aspiration (FNA) or fresh tissue can be used in this assay., Methods: Non-enzymatic tissue homogenization (IncellPREP; IncellDx, Menlo Park, California) was performed on 4-mm punch biopsies. An FNA was taken from the same tumor to create matched sample sets. Cells were labeled with antibodies directed against CD45, PD-1, and PD-L1 and then stained with DAPI to identify intact, single cells, and to analyze cell cycle., Results: Comparing the IncellPREP homogenization and FNA demonstrated a strong correlation (r 2  - 0.8) for expression of PD-L1. We compared PD-L1 expression by flow cytometry using a 1 % cutoff for positivity in the tumor cell population and a 1 % cutoff of cells with at least 1+ intensity in immunohistochemically stained tissue sections as positive. Ten of 12 lung tumor samples were concordant while 2 were discordant. PD-L1 expression by flow cytometry varied widely (1.2-89.4 %) even in the positive concordant cases. In addition, PD-L1 expression in the aneuploid tumor population did not necessarily agree with the expression in the diploid tumor population. Fine, unequivocal quantification of PD-L1 on tumor and immune cells in NSCLC may allow for better prediction of response to therapies. The present study also offers a technology that can create a universal sample type from either FNA or fresh tissue.

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., (© 2015 John Wiley & Sons Ltd.)

Myeloid neoplasms constitute one of the most common malignancies in adults. In most cases these proliferations initially manifest in the blood and marrow; however, extramedullary involvement may precede blood or marrow involvement in a subset of cases, making a definitive diagnosis challenging by morphologic and immunohistochemical assessment alone. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive entity that frequently presents in extramedullary sites and can show morphologic and immunophenotypic overlap with myeloid neoplasms. Given that BPDCN and myeloid neoplasms may both initially present in extramedullary sites and that novel targeted therapies may be developed that exploit the unique molecular signature of BPDCN, new immunophenotypic markers that can reliably separate myeloid neoplasms from BPDCN are desirable. We evaluated the utility of myeloid cell nuclear differentiation antigen (MNDA) expression in a series of extramedullary myeloid leukemias (EMLs) and BPDCN. Forty biopsies containing EML and 19 biopsies containing BPDCN were studied by MNDA immunohistochemistry. The majority of myeloid neoplasms showed nuclear expression of MNDA (65%). In contrast, all cases of BPDCN lacked MNDA expression. These findings show that MNDA is expressed in the majority of EMLs and support the inclusion of MNDA immunohistochemistry in the diagnostic evaluation of blastic hematopoietic infiltrates, particularly when the differential diagnosis is between myeloid leukemia and BPDCN.

Purpose: In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored., Patients and Methods: In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety., Results: Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event., Conclusion: Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin., Competing Interests: Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2015 by American Society of Clinical Oncology.)

Background: Standard-dose (36-Gy) total skin electron beam therapy (TSEBT) is a highly effective treatment in mycosis fungoides. However, the regimen is time-intensive and may be associated with significant toxicity., Objective: We sought to evaluate the efficacy and tolerability associated with low-dose (12-Gy) TSEBT., Methods: Data from 3 clinical trials using low-dose (12-Gy) TSEBT were pooled. In all trials, TSEBT-naïve patients with stage IB to IIIA mycosis fungoides were treated with TSEBT (12 Gy, 1 Gy per fraction over 3 weeks). The primary end point was clinical response rate. Secondary end points included time to response and duration of clinical benefit., Results: In all, 33 patients enrolled. Eighteen were male; stages were 22 IB, 2 IIA, 7 IIB, and 2 IIIA. Overall response rate was 88% (29/33), including 9 patients with complete response. Median time to response was 7.6 weeks (3-12.4 weeks). Median duration of clinical benefit was 70.7 weeks (95% confidence interval 41.8-133.8 weeks). Toxicities from TSEBT were mild and reversible., Limitations: Conclusions are limited because of the small number of patients., Conclusions: Low-dose TSEBT provides reliable and rapid reduction of disease burden in patients with mycosis fungoides, which could be administered safely multiple times during the course of a patient's disease with acceptable toxicity profile., (Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Hematopoietic stem cell transplantation (HCT), formerly known as bone marrow transplantation, is an integral part of treatment for many hematological malignancies. HCT is associated with several complications and comorbidities with differential effects on a wide spectrum of organs and tissues. We present an update on HCT-associated complications such as graft versus host disease (GVHD) and infection, with focus on the surgical pathology of the gastrointestinal (GI) tract, liver, and lung. Although the grading system for GI tract acute GVHD was proposed 40 years ago, recent studies have shed light on minimal histologic criteria for diagnosis of GVHD, as well as its differential diagnosis, including histologic effects of various medications. GI dysfunction in autologous transplant recipients is increasingly appreciated and patients are often biopsied. Acute liver injury in HCT is often due to sinusoidal obstruction syndrome (previously known as venoocclusive disease), or acute GVHD. Liver dysfunction at later time posttransplantation may be associated with acute or chronic GVHD, iron overload, or other causes of hepatitis. Lung injury in HCT is multifactorial, and it remains crucially important to diagnose and treat pulmonary infections. The pulmonary biopsy yields clinically unsuspected diagnoses in the majority of cases and its utilization is likely to increase. The pathology of the skin and kidney in HCT patients are detailed in accompanying articles.

Hematopoietic stem cell transplantation continues to be the mainstay of treatment for many hematologic dyscrasias and malignancies, including acute leukemias, lymphomas, and aplastic anemia. There can be significant complications, however, and often these complications are manifested in the skin as an eruption. Common among these are acute and chronic graft-versus-host disease, erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis, eruption of lymphocyte recovery, staphylococcal scalded skin syndrome, morbiliform drug eruptions, infections, and toxic erythema of chemotherapy. These entities can show significant clinical and histopathologic overlap, yet accurate distinctions among them are critical to initiating appropriate clinical interventions. In this review, we will discuss the key clinical and histopathologic findings in each entity as well as appropriate differential diagnostic entities.

Importance: Vismodegib is a Hedgehog signaling pathway inhibitor recently approved by the US Food and Drug Administration for advanced basal cell carcinoma. We present 2 cases of clinically significant squamous cell carcinoma within the tumor bed of locally advanced basal cell carcinoma found during vismodegib treatment., Observations: The first case is that of a patient with locally advanced basal cell carcinoma responsive to vismodegib but with an enlarging papule within the tumor bed. On biopsy, this papule was an invasive acantholytic squamous cell carcinoma. The second case is that of a patient with Gorlin syndrome with a locally advanced basal cell carcinoma that was stable while the patient was receiving therapy with vismodegib for 2.5 years but subsequently increased in size. Biopsy specimens from this tumor showed invasive squamous cell carcinoma, spindle cell subtype. In both cases, the squamous cell carcinomas were surgically resected., Conclusions and Relevance: These cases highlight the importance of repeated biopsy in locally advanced basal cell carcinomas in 2 clinical situations: (1) when an area within the tumor responds differentially to vismodegib, and (2) when a tumor stops being suppressed by vismodegib. Timely diagnosis of non-basal cell histologic characteristics is critical to institution of effective therapy.

B-cell lymphomas occurring in the skin often tend to be of systemic origin with secondary cutaneous involvement. Primary cutaneous B-cell lymphomas tend to be indolent disorders, with the exception of primary cutaneous diffuse large B-cell lymphoma-leg type (PCDLBCL-LT). In indolent conditions, the distinction between cutaneous lymphoma and cutaneous lymphoid hyperplasia can be difficult. Integration of all available information, including the clinical setting, is crucial to arriving at the appropriate diagnosis. In this review, we cover the diagnostic approaches to primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and PCDLBCL-LT, and discuss their differential diagnosis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We report 7 cases of a CD8 lymphoid proliferation of the ear and face with a cytotoxic T-cell phenotype, but an indolent clinical course. All patients presented with stable or slowly growing asymptomatic lesions on the ear, nose, or lower eyelid. Histopathology showed a dense diffuse dermal infiltrate of small- to medium-sized atypical lymphocytes without destructive features. The lymphocytes were positive for CD3, CD8, β-F1, and TIA-1 and negative for CD4, CD30, CD56, granzyme B, and PD-1. Of note, the proliferation index was low in available cases. All patients remained in complete remission at median follow-up of 14 months regardless of treatment modality. Staging was negative for extracutaneous disease in all patients. The clinically indolent behavior and histopathologic phenotype together with a low proliferation index (10%-15%) emphasize the importance of accurate diagnosis and appropriate clinical management to avoid overtreatment and complications of therapy.

Salivary gland choristoma (heterotopic salivary gland tissue) is a rare condition typically seen in the newborn period. This developmental heterotopia is generally nonprogressive, with little risk of malignant transformation. We present the second known reported case of a salivary gland choristoma located on the anterior chest wall. Knowledge of this rare entity will allow for accurate diagnosis and management of this benign anatomic variant., (© 2013 Wiley Periodicals, Inc.)

Importance: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare malignant neoplasm with cutaneous manifestations and a rapidly progressive clinical course. The diagnosis relies on characteristic clinicopathologic and immunopathologic features. However, the overlap of immunophenotypic features with other cancers, as well as newly discovered interpersonal and intrapersonal phenotypic variations, renders the identification of BPDCN challenging. A greater understanding of the proteins expressed by BPDCN might facilitate its recognition and provide insights into its clinical behavior., Observations: In 7 of 9 patients at 4 tertiary care institutions, immunohistochemical analysis demonstrated strong CD31/PECAM-1 (platelet endothelial cell adhesion molecule 1) expression by neoplastic cells. Combined with similar findings observed in 1 former patient, 8 of 10 cases of BPDCN were CD31/PECAM-1 positive., Conclusions and Relevance: Expression of CD31/PECAM-1 by BPDCN adds new information about the antigenic profile of this unusual neoplasm. CD31/PECAM-1 influences multiple cell functions including adhesion, apoptosis, coagulation, host response, and protein synthesis that might affect clinical features of BPDCN such as hemorrhage, aggressive tumor growth, and resistance to therapy. Therefore, the potential role of this molecule in the tumor formation and progression of BPDCN warrants additional exploration.

Objective: To evaluate the efficacy and safety of a novel mechlorethamine hydrochloride, 0.02%, gel in mycosis fungoides. DESIGN Randomized, controlled, observer-blinded, multicenter trial comparing mechlorethamine, 0.02%, gel with mechlorethamine, 0.02%, compounded ointment. Mechlorethamine was applied once daily for up to 12 months. Tumor response and adverse events were assessed every month between months 1 and 6 and every 2 months between months 7 and 12. Serum drug levels were evaluated in a subset of patients., Setting: Academic medical or cancer centers., Patients: In total, 260 patients with stage IA to IIA mycosis fungoides who had not used topical mechlorethamine within 2 years and were naive to prior use of topical carmustine therapy., Main Outcome Measures: Response rates of all the patients based on a primary clinical end point (Composite Assessment of Index Lesion Severity) and secondary clinical end points (Modified Severity-Weighted Assessment Tool and time-to-response analyses)., Results: Response rates for mechlorethamine gel vs ointment were 58.5% vs 47.7% by the Composite Assessment of Index Lesion Severity and 46.9% vs 46.2% by the Modified Severity-Weighted Assessment Tool. By the Composite Assessment of Index Lesion Severity, the ratio of gel response rate to ointment response rate was 1.23 (95% CI, 0.97-1.55), which met the prespecified criterion for noninferiority. Time-to-response analyses demonstrated superiority of mechlorethamine gel to ointment (P< .01). No drug-related serious adverse events were seen. Approximately 20.3% of enrolled patients in the gel treatment arm and 17.3% of enrolled patients in the ointment treatment arm withdrew because of drug-related skin irritation. No systemic absorption of the study medication was detected., Conclusion: The use of a novel mechlorethamine, 0.02%, gel in the treatment of patients with mycosis fungoides is effective and safe., Trial Registration: clinicaltrials.gov Identifier:NCT00168064.

We reviewed our multicenter experience with gamma-delta (γδ) T-cell lymphomas first presenting in the skin. Fifty-three subjects with a median age of 61 years (range, 25 to 91 y) were diagnosed with this disorder. The median duration of the skin lesions at presentation was 1.25 years (range, 1 mo to 20 y). The most common presentation was deep plaques (38 cases) often resembling a panniculitis, followed by patches resembling psoriasis or mycosis fungoides (10 cases). These lesions tended to ulcerate overtime (27 cases). Single lesions or localized areas of involvement resembling cellulitis or pyoderma were reported in 8 cases. The most common anatomic site of involvement was the legs (40 cases), followed by the torso (30 cases) and arms (28 cases). Constitutional symptoms were reported in 54% (25/46) of the patients, including some with limited skin involvement. Significant comorbidities included autoimmunity (12 cases), other lymphoproliferative disorders (5 cases), internal carcinomas (4 cases), and viral hepatitis (2 cases). Lymphadenopathy (3/42 cases) and bone marrow involvement (5/28 cases) were uncommon, but serum lactose dehydrogenase (LDH) was elevated in 55% (22/39) of the patients. Abnormal positron emission tomography and/or computed tomography scans in 20/37 subjects mostly highlighted soft tissue or lymph nodes. Disease progression was associated with extensive ulcerated lesions resulting in 27 deaths including complications of hemophagocytic syndrome (4) and cerebral nervous system involvement (3). Median survival time from diagnosis was 31 months. Skin biopsies varied from a pagetoid pattern to purely dermal or panniculitic infiltrates composed of intermediate-sized lymphocytes with tissue evidence of cytotoxicity. The most common immunophenotype was CD3+/CD4⁻/CD5⁻/CD8⁻/BF1⁻/γ-M1+/TIA-1+/granzyme-B+/CD45RA-/CD7-, and 4 cases were Epstein-Barr virus positive. This is the largest study to date of cutaneous γδ T-cell lymphomas and demonstrates a variety of clinical and pathologic presentations with a predictable poor outcome.

Sézary syndrome (SS) is an aggressive cutaneous T-cell lymphoma (CTCL) of unknown etiology in which malignant cells circulate in the peripheral blood. To identify viral elements, gene fusions, and gene expression patterns associated with this lymphoma, flow cytometry was used to obtain matched pure populations of malignant Sézary cells (SCs) versus nonmalignant CD4(+) T cells from 3 patients for whole transcriptome, paired-end sequencing with an average depth of 112 million reads per sample. Pathway analysis of differentially expressed genes identified mis-regulation of PI3K/Akt, TGFβ, and NF-κB pathways as well as T-cell receptor signaling. Bioinformatic analysis did not detect either nonhuman transcripts to support a viral etiology of SS or recurrently expressed gene fusions, but it did identify 21 SC-associated annotated long noncoding RNAs (lncRNAs). Transcriptome assembly by multiple algorithms identified 13 differentially expressed unannotated transcripts termed Sézary cell-associated transcripts (SeCATs) that include 12 predicted lncRNAs and a novel transcript with coding potential. High-throughput sequencing targeting the 3' end of polyadenylated transcripts in archived tumors from 24 additional patients with tumor-stage CTCL confirmed the differential expression of SC-associated lncRNAs and SeCATs in CTCL. Our findings characterize the SS transcriptome and support recent reports that implicate lncRNA dysregulation in human malignancies.

We describe a case of multiple, discrete, hypopigmented macules in the suprapubic and axillary region in a healthy 3-year-old girl. The lesions first appeared at approximately 9 months of age and increased in number over time. Initial histopathologic examination by an outside dermatopathologist at 1 year of age was reported as showing nonspecific histologic changes. A repeat biopsy at 3 years of age showed large intraepidermal clear cells that expressed CKAE1/CAM5.2, CK7, and BRST2. These findings are diagnostic for clear-cell papulosis, a rare condition that primarily affects children. Without great clinical and pathologic suspicion, this is a diagnosis that can often be overlooked because the histologic findings are virtually identical to those of normal skin., (© 2011 Wiley Periodicals, Inc.)

The morphologic distinction between cutaneous marginal zone lymphoma (CMZL) and secondary cutaneous involvement by B-cell chronic lymphocytic leukemia (B-CLL) can be difficult. Both entities can show very similar architectural patterns of involvement in the skin and not uncommonly, the skin can be the first site of presentation of B-CLL in the elderly. We reviewed biopsies of 13 patients with cutaneous B-CLL and 14 patients with CMZL to compare their histologic and immunohistochemical features. CMZL and cutaneous B-CLL both predominantly exhibited a nodular pattern of skin involvement (9 of 13 B-CLL, 9 of 14 CMZL) with a minority of cases demonstrating a diffuse pattern (4 of 13 B-CLL, 4 of 14 CMZL). Although reactive germinal centers (12 of 14 cases) and plasma cells (10 of 14 cases) were seen more often in CMZL, plasma cells were also observed in cases of B-CLL (4 of 13). The lesional cells of B-CLL expressed CD79, CD5, CD23, and CD43, although CMZL did not express CD5 or CD43. Although we noted light chain restriction in 13 of 14 cases of CMZL cases, we also observed light chain restriction in 4 of 13 cases of B-CLL. Our results indicate that CMZL and B-CLL can be morphologically similar and both may show light chain restriction. Complete immunophenotyping is necessary to ensure that all cases are correctly classified.

Background: A granulomatous infiltrate in association with cutaneous T-cell lymphoma is uncommon. The diagnosis of mycosis fungoides can be difficult in the setting of an exuberant granulomatous infiltrate that obscures the neoplastic lymphoid infiltrate, thereby mimicking a granulomatous dermatitis. Therefore, the clinical context and supplemental molecular analysis, such as the demonstration of a monoclonal T-cell population, may assist in diagnosis. Monoclonal T-cell populations have been reported in association with inflammatory conditions and serve as a diagnostic pitfall. The frequency of T-cell clonality in association with granulomatous dermatitides has not yet been established., Methods: We identified 29 patients with granulomatous dermatitis who had biopsies at two distinct body sites. Results were correlated with clinical follow up and with clonal T-cell receptor-gamma chain rearrangement as detected by polymerase chain reaction-based analysis (dual TCR-PCR)., Results: Clinical follow up was obtained in 17 of 29 cases (58.6%). Twenty-five of 29 cases of granulomatous dermatitis lacked T-cell monoclonality. Three cases of granuloma annulare contained a T-cell clone in one of the two biopsies. One case of necrobiotic xanthogranuloma showed an identical T-cell clone in multiple biopsies., Conclusions: The use of dual TCR-PCR analysis, that is, T-cell clonality analysis in biopsy specimens from two different sites, serves as an adjunct to assist in distinguishing granulomatous inflammatory reactions from granulomatous T-cell lymphoma, including granulomatous mycosis fungoides. The occasional finding of a T-cell clone in a granulomatous dermatitis underscores the importance of clinicopathological correlation in daily diagnosis., (2011 John Wiley & Sons A/S.)

The distinction between mycosis fungoides (MF) and inflammatory dermatoses (ID) by clinicopathologic criteria can be challenging. There is limited information regarding the performance characteristics and utility of TCRG and TCRB clonality assays in diagnosis of MF and ID from paraffin-embedded tissue sections. In this study, PCR tests were performed with both TCRG and TCRB BIOMED-2 clonality methods followed by capillary electrophoresis and Genescan analysis using DNA samples from 35 MF and 96 ID patients with 69 and 133 paraffin-embedded specimens, respectively. Performance characteristics were determined for each test individually and in combination. TCRG and TCRB tests demonstrated identical sensitivity (64%) and specificity (84%) when analyzed as individual assays. The positive predictive value, negative predictive value, and change of posttest MF probability over a range of MF pretest probabilities were obtained. These data were used to construct an algorithm for sequential use of TCRG and TCRB. As single tests, commercially available BIOMED-2 PCR-based TCRG and TCRB clonality tests on paraffin-embedded tissue have no significant difference in terms of sensitivity and specificity. Combined use of the two tests in patients with intermediate pretest probabilities as proposed in the algorithm could improve test utility.

Studies suggest that primary extranodal follicular lymphoma (FL) is not infrequent but it remains poorly characterized with variable histologic, molecular, and clinical outcome findings. We compared 27 extranodal FL to 44 nodal FL using morphologic, immunohistochemical, and molecular genetic techniques and evaluated the clinical outcome of these 2 similarly staged groups. Eight cases of primary cutaneous follicle center lymphoma were also studied. In comparison to nodal FL, a greater number of extranodal FL contained a diffuse growth pattern (P=0.004) and lacked CD10 expression (P=0.014). Fifty-four percent of extranodal and 42% of nodal FL cases showed evidence of t(14;18), with minor breakpoints (icr, 3'BCL2, 5'mcr) more commonly found in extranodal cases (P=0.003). Outcome data showed no significant differences in overall survival (P=0.565) and progression-free survival (P=0.627) among extranodal, nodal, and primary cutaneous follicle center lymphoma cases. Analysis of all cases by t(14;18) status indicate that the translocation-negative group is characterized by a diffuse growth pattern (P=0.043) and lower BCL2 expression (P=0.018). The t(14;18)-positive group showed significantly better overall survival (P=0.019) and disease-specific survival (P=0.006) in comparison with the t(14;18)-negative group. In low stage FL, the status of t(14;18) seems to be more predictive of outcome than origin from an extranodal versus nodal site.

The classification of primary cutaneous large B-cell lymphoma (PCLBCL) is based on standard morphology, immunohistochemistry, and clinical presentation. There are two major subtypes in the current WHO-EORTC classification: follicle center lymphoma and diffuse large B-cell lymphoma, leg-type (DLBCL-LT). The goals of this study were to examine a series of DLBCLs to determine (1) whether the immunohistochemical paradigm of germinal center B-cell and non-germinal center B-cell types of systemic DLBCL could be applied to PCLBCL; (2) whether application of the newly described germinal center B-cell marker, human germinal center-associated lymphoma (HGAL) also discriminates between these types as a further support for germinal center B-cell origin for primary cutaneous center lymphoma; and (3) whether any of these biologic markers were of prognostic significance. To this end, 32 cases of diffuse PCLBCL (22 primary cutaneous follicular center lymphomas and 10 DLBCL-LT) were classified based on the WHO-EORTC criteria and studied for expression of CD20, BCL2, BCL6, CD10, MUM-1, and HGAL by immunohistochemistry. Results were correlated with clinical features. HGAL and BCL6 expression and germinal center B-cell phenotype were associated with primary cutaneous follicular center lymphoma. The combination of HGAL and BCL6 positivity had the highest sensitivity (88%) and specificity (100%) for predicting subtype compared to either marker alone. Both HGAL and BCL6 were associated with the germinal center B-cell phenotype. The correlation of HGAL expression with the germinal center B-cell phenotype demonstrates the role of this marker in the classification of cutaneous large B-cell lymphomas. BCL6 expression was the only immunohistochemical marker associated with overall survival. Characterizing PCLBCLs with markers of B-cell maturation stage is a useful framework for studying, classifying, and clinically stratifying these lymphomas.

Hydroa-like lymphoma is an extremely rare and aggressive lymphoma described in children from Latin American countries (Mexico, Guatemala and Peru) and Asia (Japan, Korea and Taiwan). Clinically, patients present with vesicles, ulcers and scars occurring on both sun-exposed and non-sun-exposed areas. In contrast to classical hydroa vacciniforme, hydroa-like lymphoma is associated with systemic lymphoma of T-cell type that expresses either CD4 or CD8. We report the findings from two unusual cases of hydroa-like lymphoma that, unlike the cases described thus far in the literature, express CD56 and resemble natural killer cell lymphomas. Two 9-year-old boys presented with clinical histories of waxing and waning ulcerative blistering lesions since 3 years of age. Histological examination of skin biopsies from both cases showed periappendigeal infiltrates of atypical lymphocytes. Immunohistochemical studies showed that the cells were highlighted by markers for CD3, CD56 and CD30, but did not express CD4 and CD8. Both patients were alive with disease 1 year later. Hydroa-like lymphoma with natural killer-cell phenotype may have a similar outcome to T-cell derived hydroa-like lymphoma, but the prognosis appears to be better than classic NK lymphomas, which in general behave in an aggressive fashion.

Vascular endothelial growth factor (VEGF) exerts crucial functions during pathological angiogenesis and normal physiology. We observed increased hematocrit (60-75%) after high-grade inhibition of VEGF by diverse methods, including adenoviral expression of soluble VEGF receptor (VEGFR) ectodomains, recombinant VEGF Trap protein and the VEGFR2-selective antibody DC101. Increased production of red blood cells (erythrocytosis) occurred in both mouse and primate models, and was associated with near-complete neutralization of VEGF corneal micropocket angiogenesis. High-grade inhibition of VEGF induced hepatic synthesis of erythropoietin (Epo, encoded by Epo) >40-fold through a HIF-1alpha-independent mechanism, in parallel with suppression of renal Epo mRNA. Studies using hepatocyte-specific deletion of the Vegfa gene and hepatocyte-endothelial cell cocultures indicated that blockade of VEGF induced hepatic Epo by interfering with homeostatic VEGFR2-dependent paracrine signaling involving interactions between hepatocytes and endothelial cells. These data indicate that VEGF is a previously unsuspected negative regulator of hepatic Epo synthesis and erythropoiesis and suggest that levels of Epo and erythrocytosis could represent noninvasive surrogate markers for stringent blockade of VEGF in vivo.

Background: Distinction between cellular fibrous histiocytomas (FHs) with a deep component and dermatofibrosarcoma protuberans (DFSPs) can pose diagnostic problems. While CD68, CD34, and Factor XIIIa are helpful in distinguishing between these entities, none are diagnostically absolute. Recent work with CD163, a hemoglobin scavenger receptor, has demonstrated that this marker has high specificity for monocytes, macrophages, and histiocytes. Our goal is to evaluate the utility of CD163 in the diagnosis of dermatofibromas (DFs), cellular FHs, and DFSPs., Methods: Sixty cases including 19 DFs, 23 cellular FHs with a deep component, and 18 DFSPs were tested with antibodies against CD163, CD68, CD34, and Factor XIIIa., Results: CD163 was expressed in 17/19 (89%) DFs, 23/23 (100%) cellular FHs, and 3/18 (17%) DFSPs. CD68 was positive in 8/19 (42%) DFs, 19/23 (83%) cellular FHs, and 1/16 (6%) DFSPs. CD34 was expressed in 1/19 (5%) DFs, 5/23 (22%) cellular FHs, and 100% of DFSPs. Factor XIIIa labeled 4/19 (21%) DFs, 11/23 (48%) cellular FHs, and 0/17 cases of DFSPs., Conclusions: CD163 expression is helpful in distinguishing between cellular FHs and DFSPs and will be useful in a panel of antibodies when these entities are in the differential diagnosis. Sachdev R, Sundram U. Expression of CD163 in dermatofibroma, cellular fibrous histiocytoma, and dermatofibrosarcoma protuberans: comparison with CD68, CD34, and Factor XIIIa.

Cutaneous manifestations of acute promyelocytic leukemia are rare but well documented. Skin biopsies of leukemia can be difficult to confirm using morphology alone, and paraffin section immunophenotyping is not specific in separating acute promyelocytic leukemia from other acute myeloid leukemias involving the skin or inflammatory conditions, such as Sweet's syndrome and all-trans retinoic acid-associated genital ulcers, which may mimic leukemia cutis. Fluorescence in situ hybridization has been shown to be a fast and effective method of detecting the PML/RARA fusion gene characteristic of acute promyelocytic leukemia in fresh blood and bone marrow samples. Fluorescence in situ hybridization has also been demonstrated to be effective in detecting other chromosomal rearrangements in paraffin-embedded tissue. This retrospective study of cutaneous lesions from four patients with acute promyelocytic leukemia evaluates the utility of performing fluorescence in situ hybridization to confirm the presence of cutaneous manifestations of acute promyelocytic leukemia in formalin-fixed, paraffin-embedded skin biopsies. All patients had previous bone marrow findings of acute promyelocytic leukemia with characteristic morphology, immunophenotype, and cytogenetic studies, which detailed the presence of the t(15;17)(q22;q12) rearrangement. Two skin biopsies showed an infiltrate of blastic cells involving the dermis in a diffuse pattern and one biopsy had a perivascular/periadnexal pattern. The fourth case, involving the scrotum, showed a predominant neutrophilic infiltrate diffusely involving the dermis and epidermis with a subset of blastic cells. Nuclei were extracted from core biopsies of the formalin-fixed paraffin-embedded tissue and fluorescence in situ hybridization was performed using a dual color, dual fusion PML / RARA probe. All cases showed evidence of the t(15;17) rearrangement, with 90, 79, 51 and 16% positive signal patterns, each well above background limits. Fluorescence in situ hybridization appears to be a robust technique to detect cutaneous manifestations of acute promyelocytic leukemia in formalin-fixed paraffin-embedded skin biopsies.

Background: Systemic B-cell lymphomas have been studied using microarrays, which has led to a better understanding of their molecular characteristics. Initial microarray studies of these lymphomas have implicated several genes as important predictors of outcome. In this study, we used a tissue microarray (TMA) to characterize primary cutaneous large B-cell lymphomas (PCLBCL)., Methods: We studied 14 patients for whom clinical follow up was available, including four patients whose lesions were limited to the leg on presentation. Immunohistochemical staining with CD20, CD44, CD21, CD5, CD10, bcl-2, bcl-6, Ki67, p53, and multiple myeloma 1 (MUM1) was examined., Results: Our results identify two subgroups of lymphomas. The first group showed staining with bcl-6 and had an overall survival of 176 months (p = 0.003). The majority of this group was negative for MUM1. The second group lacked staining with bcl-6 and had an overall survival of 26 months, with a majority of these cases staining with MUM1. Three of four patients with PCLBCL of the leg showed no staining with bcl-6., Conclusions: Our study demonstrates the utility of TMAs in the analysis of PCLBCL and that expression of bcl-6 and MUM1 correlates with survival.

Soluble receptors to vascular endothelial growth factor (VEGF) can inhibit its angiogenic effect. Since angiogenesis is involved in wound repair, we hypothesized that adenovirus-mediated gene transfer of a soluble form of VEGF receptor 2 (Flk-1) would attenuate wound healing in mice. C57Bl/6J and genetically diabetic (db/db) mice (each n=20) received intravenous (i.v.) injections of recombinant adenoviruses (10(9) PFU) encoding the ligand-binding ectodomain of VEGF receptor 2 (Flk-1) or cDNA encoding the murine IgG2alpha Fc fragment (each n=10). At 4 days after gene transfer, two full-thickness skin wounds (0.8 cm) were created on the dorsum of each animal. Wound closure was measured over 9-14 days after which wounds were resected for histological analysis. Prior to killing, fluorescent microspheres were systemically injected for quantitation of wound vascularity. Single i.v. injections of adenoviruses encoding soluble Flk-1 significantly decreased wound angiogenesis in both wild-type and diabetic mice. Fluorescence microscopy revealed a 2.0-fold (wild type) and 2.9-fold (diabetic) reduction in wound vascularity in Flk-1-treated animals (p<0.05). Impairment of angiogenesis was confirmed by CD31 immunohistochemistry. Interestingly, despite significant reductions in wound vascularity, wound closure was not grossly delayed. Our data indicates that while VEGF function is essential for optimal wound angiogenesis, it is not required for wound closure.

The diagnosis of malignant melanoma remains one of the most difficult to render in surgical pathology, partially because of its extreme histologic variability. Limits in the sensitivity and/or specificity of the currently available melanocytic markers such as anti-S100, HMB45, and anti-MelanA further complicate this problem. Previous work has demonstrated that the B-cell proliferation/differentiation marker MUM1/IRF4 is detected in malignant melanoma and hematolymphoid malignancies, but not in any other neoplasm tested (including colonic, lung, breast, and ovarian carcinomas). In the current study, we have examined MUM1 protein expression in 61 melanocytic lesions and compared the diagnostic usefulness of this marker with that of anti-S100, HMB45, and anti-MelanA. The results indicate that MUM1 is positive in 33/36 (92%) cases of melanoma (21/22 [95%] conventional primary melanomas and 12/14 [86%] metastatic melanomas). In comparison, positivity was seen with anti-S100 in 36/36 cases (100%, 22 primary and 14 metastatic), HMB45 in 28 cases (78%, 17 primary and 11 metastatic), and anti-MelanA in 27 cases (75%, 19 primary and 8 metastatic). Although negative in schwannomas, neurofibromas, and malignant peripheral nerve sheath tumors, MUM1 is detected in only one in eight cases of spindle cell and desmoplastic melanomas. With the exception of desmoplastic and spindle cell melanomas, MUM1 appears to be a sensitive and specific immunohistochemical stain for melanocytic lesions and may prove to be a useful addition to the current panel of melanoma markers.

Background: Antibodies to CD4, CD8, TIA-1, and CD56 are available which perform well in formalin-fixed and paraffin-embedded tissue. While previous studies have investigated CD4 and CD8 subsets in inflammatory skin disease, few have specifically addressed TIA-1 and CD56 reactivity in benign dermatoses. Given that CD8, TIA-1, and CD56 are linked to aggressive lymphoproliferative disorders (i.e. subcutaneous panniculitic T-cell lymphoma, natural killer (NK), and NK/T-cell lymphomas), it would be important to determine their specificity for cutaneous hematologic malignancies. This investigation was undertaken to determine the frequency with which common, benign dermatoses express these four markers. We also sought to determine whether the ratio of CD4- to CD8-positive cells could be used to distinguish among the dermatoses, especially the superficial and deep perivascular ones., Methods: Formalin-fixed and paraffin-embedded sections from a variety of common inflammatory dermatoses were stained with antibodies to CD4, CD8, TIA-1, and CD56. Positive reactions were scored as a percentage of the entire mononuclear cell infiltrate., Results: All of the dermatoses represented in the study showed TIA-1- and CD56-positive lymphocyte subpopulations. On a case-by-case basis, the percentage of positive cells varied, and while all cases were positive for TIA-1, many were completely negative for CD56. For TIA-1, the percentage of positive cells ranged from 21 to 59%, and for CD56, from < 1 to 9%. The CD4:CD8 ratio ranged from 1.0 to 6.0 but was never less than 1.0. In addition to lymphocytes, TIA-1 also stained polymorphonuclear leukocytes, eosinophils, and mast cells., Conclusion: TIA-1- and CD56-positive lymphocytes are common participants in routine inflammatory dermatoses, and therefore these markers are not specific for aggressive lymphoproliferative disorders. Using only immunohistochemical data, the ratio of CD4- to CD8-positive lymphocytes could not be used reliably to separate the superficial and deep perivascular dermatoses from one another. Finally, mast cells are positive for TIA-1 and are commonly seen in normal and inflamed skin, and thus TIA-1 is not specific for cytotoxic T lymphocytes.