Publications by authors named "Uma Sundram"

63 Publications

Appropriate use criteria for ancillary diagnostic testing in dermatopathology: New recommendations for 11 tests and 220 clinical scenarios from the American Society of Dermatopathology Appropriate Use Criteria Committee.

J Cutan Pathol 2021 Sep 18. Epub 2021 Sep 18.

Department of Pathology, Cleveland Clinic, Cleveland, Ohio, USA.

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.
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http://dx.doi.org/10.1111/cup.14135DOI Listing
September 2021

Kappa and lambda immunohistochemistry and in situ hybridization in the evaluation of atypical cutaneous lymphoid infiltrates.

J Cutan Pathol 2020 Nov 14;47(11):1103-1110. Epub 2020 Sep 14.

Department of Pathology, Oakland University William Beaumont School of Medicine and Beaumont Health Systems, Royal Oak, Michigan, USA.

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.
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http://dx.doi.org/10.1111/cup.13858DOI Listing
November 2020

Cutaneous Lymphoproliferative Disorders: What's New in the Revised 4th Edition of the World Health Organization (WHO) Classification of Lymphoid Neoplasms.

Authors:
Uma Sundram

Adv Anat Pathol 2019 Mar;26(2):93-113

Department of Anatomic Pathology, Oakland University William Beaumont School of Medicine and Beaumont Health Systems, Royal Oak, MI.

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.
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http://dx.doi.org/10.1097/PAP.0000000000000208DOI Listing
March 2019

Concordance of somatic mutation profiles (BRAF,NRAS, and TERT) and tumoral PD-L1 in matched primary cutaneous and metastatic melanoma samples.

Hum Pathol 2018 12 16;82:206-214. Epub 2018 Aug 16.

Dermatopathology Section, VA Integrated Systems Network (VISN1), Department of Pathology and Laboratory Medicine, West Roxbury, MA 02132, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.humpath.2018.08.002DOI Listing
December 2018

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

J Am Acad Dermatol 2019 Jan 22;80(1):189-207.e11. Epub 2018 Apr 22.

Departments of Pathology, Dermatology, and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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.
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http://dx.doi.org/10.1016/j.jaad.2018.04.033DOI Listing
January 2019

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

J Cutan Pathol 2018 Aug 7;45(8):563-580. Epub 2018 Jun 7.

Bey Dermatology and Cosmetic Surgery, Spring Hill, Florida.

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.
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http://dx.doi.org/10.1111/cup.13142DOI Listing
August 2018

Cutaneous lymphoma.

J Clin Pathol 2018 Feb 16;71(2):185-186. Epub 2017 Nov 16.

Oakland University William Beaumont School of Medicine, Pathology, Royal Oak, Michigan, USA.

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http://dx.doi.org/10.1136/jclinpath-2016-204009DOI Listing
February 2018

Views of dermatopathologists about clonality assays in the diagnosis of cutaneous T-cell and B-cell lymphoproliferative disorders.

J Cutan Pathol 2018 Jan 22;45(1):39-47. Epub 2017 Nov 22.

Department of Dermatology, University of Iowa, Iowa City, Iowa.

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.
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http://dx.doi.org/10.1111/cup.13072DOI Listing
January 2018

Localized skin-limited blastic plasmacytoid dendritic cell neoplasm: A subset with possible durable remission without transplantation.

JAAD Case Rep 2017 Jul 19;3(4):310-315. Epub 2017 Jul 19.

Department of Dermatology, Stanford Cancer Center, Stanford Hospital and Clinics, Stanford, California, USA.

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http://dx.doi.org/10.1016/j.jdcr.2017.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517837PMC
July 2017

GATA3 and MYB Expression in Cutaneous Adnexal Neoplasms.

Am J Dermatopathol 2017 Apr;39(4):279-286

*Departments of Pathology, Porto Medical School and Sao Joao Hospital, Porto, Portugal; †Departments of Pathology, William Beaumont School of Medicine, Royal Oak, MI; ‡Departments of Pathology, Duke University Medical Center, Durham, NC; and §Departments of Pathology, Harvard Medical School and Massachusetts General Hospital, Boston, MA.

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.
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http://dx.doi.org/10.1097/DAD.0000000000000634DOI Listing
April 2017

Quantification of PD-L1 and PD-1 expression on tumor and immune cells in non-small cell lung cancer (NSCLC) using non-enzymatic tissue dissociation and flow cytometry.

Cancer Immunol Immunother 2016 11 26;65(11):1317-1323. Epub 2016 Aug 26.

IncellDx, Inc., 1700 El Camino Real, Menlo Park, CA, 94027, USA.

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  - 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.
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http://dx.doi.org/10.1007/s00262-016-1889-3DOI Listing
November 2016

Myeloid Cell Nuclear Differentiation Antigen (MNDA) Expression Distinguishes Extramedullary Presentations of Myeloid Leukemia From Blastic Plasmacytoid Dendritic Cell Neoplasm.

Am J Surg Pathol 2016 Apr;40(4):502-9

*Department of Pathology, Stanford University, Stanford, CA †Department of Pathology, The Ohio State University, Columbus, OH ‡Department of Pathology, Oregon Health & Science University, Portland, OR.

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.
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http://dx.doi.org/10.1097/PAS.0000000000000595DOI Listing
April 2016

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

Histopathology 2016 Jul 1;69(1):11-9. Epub 2016 Mar 1.

Dundee Cancer Centre, Ninewells Hospital and Medical School, Dundee, UK.

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.
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http://dx.doi.org/10.1111/his.12855DOI Listing
July 2016

Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project.

J Clin Oncol 2015 Nov 20;33(32):3750-8. Epub 2015 Jul 20.

Youn H. Kim, Mahkam Tavallaee, Uma Sundram, Shufeng Li, Sima Rozati, Seema Nagpal, Michael Krathen, Sunil Reddy, Richard T. Hoppe, Annie Nguyen-Lin, Wen-Kai Weng, Randall Armstrong, and Ranjana H. Advani, Stanford University, Stanford, CA; Katrin A. Salva and Gary S. Wood, University of Wisconsin and William S. Middleton Memorial Veterans Hospital, Madison, WI; and Melissa Pulitzer and Steven M. Horwitz, Memorial Sloan Kettering Cancer Center, New York, NY.

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.
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http://dx.doi.org/10.1200/JCO.2014.60.3969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089160PMC
November 2015

The vascular marker CD31 also highlights histiocytes and histiocyte-like cells within cutaneous tumors.

Am J Clin Pathol 2015 Feb;143(2):177-85; quiz 305

From the Departments of Pathology, Stanford University Medical Center, Stanford, CA. From the Departments of Dermatology, Stanford University Medical Center, Stanford, CA.

Objectives: While useful in diagnosing angiosarcomas, CD31 can also highlight histiocytes within soft tissue tumors and lead to errors in diagnosis. We sought to determine how often CD31 highlights cutaneous histiocytomas and histiocytoma mimics.

Methods: We examined eight epithelioid cell histiocytomas (ECHs), 12 xanthogranulomas (XGs), nine cases of Langerhans cell histiocytosis (LCH), eight reticulohistiocytomas, 11 xanthomas, 29 atypical fibroxanthomas, nine granular cell tumors, four cases of angiolymphoid hyperplasia with eosinophilia, nine intradermal Spitz nevi, and nine angiosarcomas with antibodies directed against CD31, CD34, CD163, and factor VIII.

Results: CD31 marked cells in three of 12 XGs, four of nine cases of LCH, one of eight reticulohistiocytomas, one of 11 xanthomas, 10 of 29 atypical fibroxanthomas, four of four cases of angiolymphoid hyperplasia with eosinophilia, nine of nine angiosarcomas, zero of nine granular cell tumors, and zero of eight ECHs. CD34 and factor VIII were negative in all nonvascular cases.

Conclusions: Our results indicate that CD31 can mark lesional cells and imitate vascular tumors in cutaneous histiocytomas and histiocytoma mimics, an error that can be avoided by using a panel of antibodies.
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http://dx.doi.org/10.1309/AJCPRHM8CZH5EMFDDOI Listing
February 2015

Low-dose total skin electron beam therapy as an effective modality to reduce disease burden in patients with mycosis fungoides: results of a pooled analysis from 3 phase-II clinical trials.

J Am Acad Dermatol 2015 Feb 2;72(2):286-92. Epub 2014 Dec 2.

Department of Dermatology, Stanford Cancer Institute, Stanford, California.

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.
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http://dx.doi.org/10.1016/j.jaad.2014.10.014DOI Listing
February 2015

A review of important skin disorders occurring in the posttransplantation patient.

Authors:
Uma Sundram

Adv Anat Pathol 2014 Sep;21(5):321-9

Departments of *Pathology †Dermatology, Stanford University Medical Center, Stanford, CA.

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.
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http://dx.doi.org/10.1097/PAP.0000000000000033DOI Listing
September 2014

Hematopoietic stem cell transplantation: graft versus host disease and pathology of gastrointestinal tract, liver, and lung.

Adv Anat Pathol 2014 Sep;21(5):301-20

*Department of Pathology, Stanford University School of Medicine, Stanford, CA †Department of Pathology, Oregon Health and Science University, Portland, OR.

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.
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http://dx.doi.org/10.1097/PAP.0000000000000032DOI Listing
September 2014

Primary Cutaneous B-Cell Lymphomas.

Authors:
Uma Sundram

Surg Pathol Clin 2014 Jun 12;7(2):253-83. Epub 2014 Apr 12.

Department of Pathology, Stanford Hospital and Clinics, 300 Pasteur Drive Room H2117, Stanford, CA 94305, USA; Department of Dermatology, Stanford Hospital and Clinics, 450 Broadway, Pavilion B 4th Floor, Redwood City, CA 94063, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.path.2014.02.002DOI Listing
June 2014

Two different scenarios of squamous cell carcinoma within advanced Basal cell carcinomas: cases illustrating the importance of serial biopsy during vismodegib usage.

JAMA Dermatol 2014 Sep;150(9):970-3

Department of Dermatology, Stanford University School of Medicine, Redwood City, California.

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.
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http://dx.doi.org/10.1001/jamadermatol.2014.583DOI Listing
September 2014

Multicenter case series of indolent small/medium-sized CD8+ lymphoid proliferations with predilection for the ear and face.

Am J Dermatopathol 2014 May;36(5):402-8

*Department of Medicine, Dermatology Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY; †Department of Dermatology, Northwestern University, Chicago, IL; ‡Department of Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY; §Department of Dermatology and Pathology, Yale University, New Haven, CT; Departments of ¶Pathology, and ‖Dermatology, Stanford University, Stanford, CA; and **Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY.

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.
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http://dx.doi.org/10.1097/DAD.0b013e3182a74c7aDOI Listing
May 2014

Expression of CD31/PECAM-1 (platelet endothelial cell adhesion molecule 1) by blastic plasmacytoid dendritic cell neoplasms.

JAMA Dermatol 2014 Jan;150(1):73-6

Department of Dermatology, University of Wisconsin, Madison.

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.
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http://dx.doi.org/10.1001/jamadermatol.2013.7141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058994PMC
January 2014

Salivary gland choristoma (heterotopic salivary gland tissue) on the anterior chest wall of a newborn.

Pediatr Dermatol 2014 Jan-Feb;31(1):e36-7. Epub 2013 May 16.

Department of Pediatrics, Stanford University School of Medicine, Stanford, California.

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.
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http://dx.doi.org/10.1111/pde.12159DOI Listing
September 2014

Diagnostic utility of Fli-1 and D2-40 in distinguishing atypical fibroxanthoma from angiosarcoma.

Am J Dermatopathol 2013 May;35(3):316-8

Department of Pathology, Stanford University Medical Center, Stanford, CA, USA.

Although in most cases one can easily distinguish between atypical fibroxanthomas and angiosarcomas, hemorrhagic atypical fibroxanthomas can pose a diagnostic problem. In rare cases, the large atypical cells of atypical fibroxanthoma can stain with CD31, leading to the erroneous diagnosis of angiosarcoma. We elected to further study this conundrum with 2 additional markers of lymphatic and vascular elements, namely D2-40 (podoplanin) and Fli-1, respectively. We studied 26 cases of atypical fibroxanthoma and 20 cases of angiosarcoma with Fli-1 and D2-40. We found that both Fli-1 and D2-40 stained a majority of cases of angiosarcoma (16/20 and 12/20, respectively), although only staining a minority of cases of atypical fibroxanthoma (8/26 for both). In addition, D2-40 staining of atypical fibroxanthoma was usually weak when positive, whereas Fli-1 staining of angiosarcomas was mostly strong and nuclear. Thus, both D2-40 and Fli-1 seem to be useful in distinguishing between atypical fibroxanthomas and angiosarcomas.
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http://dx.doi.org/10.1097/DAD.0b013e318266b197DOI Listing
May 2013

Diagnosing epidermolysis bullosa type and subtype in infancy using immunofluorescence microscopy: the Stanford experience.

Pediatr Dermatol 2013 Mar-Apr;30(2):226-33

Division of Dermatology, Department of Medicine, Washington University, St. Louis, Missouri, USA.

The natural history of inherited epidermolysis bullosa (EB) varies significantly across subtypes. When confronted with an infant suspected to have EB, rapidly determining the type and subtype is critical in counselling families accurately about the infant's diagnosis and prognosis. Although transmission electron microscopy (TEM) has been considered the criterion standard for EB diagnosis, immunofluorescence microscopy (IFM) using monoclonal antibodies (mAbs) to EB-specific basement membrane zone proteins has several advantages, but few studies have evaluated the diagnostic utility of IFM. We sought to evaluate the clinical utility of IFM using an expanded panel of EB-specific mAbs. This was a retrospective review of pathology reports from infants younger < 1 year old with suspected EB primarily analyzed with IFM by the Stanford Dermatopathology service. Seventy-seven cases were identified for analysis, of which 20 were suboptimal for IFM analysis. Fifty-five cases were diagnosed with EB and classified as follows: EB simplex (n = 5), junctional EB (n = 31), dystrophic EB (n = 19). TEM was available in 36 of 55 cases (65%). IFM with an expanded panel of EB-specific mAbs should be considered the first-line diagnostic test to evaluate infants with clinically suspected EB.
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http://dx.doi.org/10.1111/j.1525-1470.2012.01880.xDOI Listing
September 2013

Cutaneous γδ T-cell lymphomas: a spectrum of presentations with overlap with other cytotoxic lymphomas.

Am J Surg Pathol 2012 Nov;36(11):1656-65

Department of Dermatology and Pathology, Northwestern University Feinberg Medical School, Chicago, IL 60091, USA.

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.
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http://dx.doi.org/10.1097/PAS.0b013e31826a5038DOI Listing
November 2012

Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides.

JAMA Dermatol 2013 Jan;149(1):25-32

Division of Dermatology, Department of Pathology, Fox Chase Cancer Center, University of Pennsylvania, Philadelphia, USA.

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.
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http://dx.doi.org/10.1001/2013.jamadermatol.541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662469PMC
January 2013

Reconsidering the diagnostic and prognostic utility of LN-2 for undifferentiated pleomorphic sarcoma and atypical fibroxanthoma.

Am J Dermatopathol 2013 Apr;35(2):176-9

Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.

The topic of distinguishing atypical fibroxanthoma (AFX) from undifferentiated pleomorphic sarcoma (UPS), formerly malignant fibrous histiocytoma, is highly controversial. Although their clinical behavior is disparate, AFX and UPS commonly appear nearly identical on routine histopathologic examination. Although conceptually useful, subcategorization of UPS into superficial (confined to the dermis and subcutaneous tissue) and deep (involvement of fascia and deeper structures) types has not improved our ability to differentiate UPS from AFX. Numerous authors have purported LN-2 (CD74) immunopositivity as able to distinguish UPS from AFX and to predict those rare AFX likely to behave aggressively, although only a single prior study has been dedicated to evaluating this marker. We performed LN-2 staining of 14 AFX, 8 superficial UPS, and 65 deep UPS specimens using an identical protocol as described by prior authors. Of the 73 total UPS specimens, only 1 (1.4%) stained strongly with LN-2, as compared with 3 of 14 (21%) AFX (P = 0.012). One of 2 (50%) clinically aggressive AFX tumors that later exhibited both local recurrence and metastasis stained strongly for LN-2, whereas 2 of 12 (17%) of the more indolent tumors stained strongly with this marker (P = 0.40). Our data do not replicate prior reports of LN-2 as a sensitive and specific marker for UPS, or as indicative of prognosis for AFX, and therefore does not support the use of LN-2 as either a diagnostic or prognostic marker.
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http://dx.doi.org/10.1097/DAD.0b013e318265fb9eDOI Listing
April 2013

Transcriptome sequencing in Sezary syndrome identifies Sezary cell and mycosis fungoides-associated lncRNAs and novel transcripts.

Blood 2012 Oct 30;120(16):3288-97. Epub 2012 Aug 30.

Programs in Epithelial Biology, Department of Dermatology, Stanford University, CA, USA.

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.
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http://dx.doi.org/10.1182/blood-2012-04-423061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3476540PMC
October 2012

Discordant immunophenotypic profiles of adhesion molecules and cytokines in acute myeloid leukemia involving bone marrow and skin.

Am J Clin Pathol 2012 Aug;138(2):290-9

Department of Pathology, Stanford University Medical Center, CA 94305, USA.

We investigated the role of adhesion molecules in skin involvement by acute myeloid leukemia (AML) using immunohistochemical analysis. Ten paired cases of skin and bone marrow biopsy specimens from patients with myeloid leukemia cutis (MLC) and 15 bone marrow biopsy specimens from patients without MLC were studied with antibodies directed against CD29, CD34, CD54, CD62-L, CD183, and cutaneous lymphocyte antigen (CLA). CLA was expressed in all cases of leukemia whereas CD54 was negative within blasts. CD62-L was expressed in 4 of 10 specimens of marrow infiltrates with MLC and 6 of 10 specimens of matching skin infiltrates; in marrows without MLC, only 2 of 15 were positive. CD29 was expressed in 1 of 10 marrow infiltrate specimens with MLC and 4 of 10 matching skin infiltrate specimens; in marrows without MLC, only 1 of 15 were positive. CD183 was expressed in 1 of 10 marrow infiltrate specimens with MLC and 4 of 10 matching skin infiltrate specimens; in marrows without MLC, CD183 was negative. The gain of CD62-L, CD29, and CD183 expression in bone marrow and skin infiltrates in leukemia cutis, relative to bone marrow infiltrates of cases without MLC, suggests a role for these markers in AML homing to skin.
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http://dx.doi.org/10.1309/AJCP34YERPZSCYKQDOI Listing
August 2012
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