#dermpathJC February 2021 summary

#dermpathJC February 2021:

Thursday, February 25th, 9pm EST

Article discussed:  Erythema Migrans and Interface Changes: More Than a Fortuitous Association

Authors: Tekin, Burak MD; Song, Yali MD; DiCostanzo, Damian MD; Lee, Bonnie A. MD

Temporary free access courtesy of The American Journal of Dermatopathology: https://journals.lww.com/amjdermatopathology/pages/articleviewer.aspx?year=2020&issue=10000&article=00004&type=Fulltext

Summary prepared by: Shaymaa Ashi, MD (@shaymaloh)

Journal Club Summary:

Introduction:

  • This article reviewed the histopathologic characteristic of erythema chronicum migrans (ECM), with emphasis on the classical features and observation of new patterns.
  • ECM represents the cutaneous manifestation of early Lyme disease. It typically presents with polycyclic targetoid rash with erythematous border and central clearing. Fully developed lesions usually measure >5 cm.  It is usually localized; but can be disseminated (25%).
  • Diagnosis is made based on clinical findings (characteristic clinical lesions, history of tick bite) and response to treatment. Serology has low sensitivity in early Lyme disease.  PCR can be used for confirmation.
  • Biopsy is warranted when the clinical presentation is atypical (vesicular, bullous, or hemorrhagic/purpuric rash, no history of tick bite) to confirm ECM and exclude other entities in the differential diagnosis (viral exanthems, arthropod bite reaction, erythema nodosum, drug eruption, gyrate erythema, dermatitis, and tinea).
  • Classic histopathologic features are superficial to deep perivascular inflammatory infiltrate, mainly of lymphocytes, associated with plasma cells and eosinophils.
  • Some studies state that variations in histomorphology can occur, including interface dermatitis, spongiosis, necrotic keratinocytes, absence of plasma cells.

Summary of current study methodology and results:

  • The aim of this study is to detect the frequency of variable histopathologic findings in ECM lesions to increase the diagnostic sensitivity of biopsy, usually performed to establish the diagnosis in cases with atypical clinical presentations.
  • Two dermatopathologists evaluated biopsies from a cohort of 14 cases with clinically and/or serologically confirmed Lyme disease from the archives of 2 institutions located in Lyme disease endemic area (Ackerman Academy of Dermatopathology and Dermpath Diagnostics in New York). The most prominent histopathological changes detected are summarized as follows:
  • All 14 cases demonstrated a superficial perivascular lymphocytic infiltrate.
    • 5/14 cases (36%) did not have any additional changes
    • 11/14 cases (64%) showed additional interstitial and/or deep perivascular lymphocytic infiltrate
    • The density of the infiltrate was variable (sparse to markedly dense). Nodular or pseudolymphomatous infiltrates were not identified as opposed to other studies
    • 12/14 cases (86%) showed interface changes, ranging from focal to diffuse
    • 2/14 cases (14%) showed necrotic keratinocytes
    • 2/14 cases (14%) showed mild spongiosis
    • 7/14 cases (50%) showed eosinophils
    • 10/14 case (71%) showed plasma cells
    • 3/14 cases (21%) showed extravasated RBCs
A-C Focal interface dermatitis, papillary dermal edema and extravasated RBCs. D: lymphocyte exocytosis to basal layer. Arrows in A-D: elongated squiggly lymphocytes

Summary of literature review:

  • Berger et al (1983): Some cases (24%) show lymphocytes blurring of the dermo-epidermal junction (44%) and extend to epidermis (21%)
  • de Koning (1983): Some cases have lymphocytes disrupting the dermo-epidermal junction and the basement membrane
  • Böer et al (2007): Vacuolar degeneration seen in 8/34 cases, lymphocytes seen in basal layer (15/34), and in suprabasal epidermal levels (7/34)
  • Wilson et al (2012): Interface/vacuolar change seen in 2/4 cases (50%)
  • Miraflor et al (2016): Interface change seen in 3/8 cases (38%)

Discussion points:

  • Interface dermatitis, focal to diffuse, with sparse perivascular lymphocytic infiltrates, is seen in a high percentage of ECM biopsies, and scrutiny is needed in examining the tissue to look for subtle/focal interface changes, to avoid missing ECM cases in the earlier phase when serology tends to be negative.
  • This study has higher percentage of ECM cases with interface dermatitis (86%) compared to the other studies mentioned in the literature review.  
  • More than 50% of the cases in this study had only focal interface changes.
  • The density of the dermal infiltrates is variable.
  • The center of early lesions has more eosinophils, while the periphery has more plasma cells. This study had comparable results to those of Miraflor et al study regarding plasma and eosinophils percentage, while Wilson et al indicated absence of plasma cells in his case cohort and Boer et al indicated plasma cells were unreliable criterion for ECM diagnosis.
  • A new observation in this study is that reactive lymphocytes seen in biopsies from infections are elongated and squiggly, correlating with findings of ultrastructural studies of reactive T lymphocytes.
  • The limitation of this study: retrospective study design, diagnosis was not uniformly confirmed in all cases by serology or PCR, site of biopsies (center versus periphery) was not indicated.
  • ECM can have variable histopathologic manifestations and should be included in the differential diagnosis of sparsely inflamed biopsies and those with subtle/focal interface dermatitis.

Memorable Tweets:

And now a SPECIAL interview with Dr Bonnie Lee (senior author of ECM paper) on the ASDP YouTube channel: Dr Silvija Gottesman and Dr Jisun Cha’s #DermpathJC​ Q&A session with Dr Bonnie Lee about the histologic findings of Erythema Chronicum Migrans, a characteristic cutaneous eruption that appears in the early stages on Lyme disease.

Until next month #dermpathJC, stay safe!

#dermpathJC January 2021 summary

#dermpathJC January 2021:

Thursday, January 28th, 9pm EST

Article discussed: Histopathologic evaluation of nail lichen planus: A cross-sectional study

Authors: Geetali Kharghoria, MD, DNB, Chandra Grover MD, DNB, MNAMS, Sambit Nath Bhattacharya, MD, Sonal Sharma, MD

and

Editorial: The “frayed nail plate” and further detailed analysis of the histopathologic features of nail unit lichen planus from Dr Adam I. Rubin, MD

Temporary free access courtesy of the Journal of Cutaneous Pathology:

https://onlinelibrary.wiley.com/doi/full/10.1111/cup.13783

https://doi.org/10.1111/cup.13845

Summary prepared by:  Parneet Dhaliwal, DO (@FollowPath)

Journal Club Summary:

INTRODUCTION

  • Nail involvement can be seen in up to 10% of patients with lichen planus (LP)
  • Fingernails are affected more often than toenails
  • Any part of the nail can be involved, but the nail matrix is characteristic of nail lichen planus (90% of cases) and can present as “longitudinal striations, thinning of nail plate, dorsal pterygium, or trachyonychia.”
  • The disease course progresses slowly but surely, and many patients develop scarring, anonychia, and pterygium formation.
  • Zaias first described histopathology of nail LP in 1970:
    • Hyperkeratosis
    • Hypergranulosis
    • Papillary dermis with band-like lymphocytic infiltrate
    • Basal layer degeneration
    • Colloid bodies
    • Pigment incontinence (melanophages)
  • Major and minor criteria of nail LP:

PATIENTS AND METHODS

  • 45 patients from Department of Dermatology and Venereology and Pathology at a teaching hospital in Dehli, India were recruited, consented, and screened
  • Nail biopsy of most representative site was preformed (nail bed vs nail matrix)
  • Major and minor criteria were applied to the biopsies

RESULTS

  • Patient population
    • N=45
    • Mean age: 36.91 +/- 18.27 years
    • M>F (male predominance 64%)
    • Mean disease duration: 29.07 +/ 25.85 months
  • Clinical LP presentations:
    • Oral mucosa LP – 51%
    • Genital involvement – 0%
    • Isolated nail LP – 29%
    • Generalized LP – 28.8%
    • Linear LP – 6.6%
    • Lichen planopilaris (cicatricial alopecia) involving the scalp – 6.6%
    • Palmoplantar LP – 2.2%
    • LP pigmentosus – 2.2%
  • Most common presenting symptom: brittleness or fragility – 40%
  • Nails involved: 8.13 +/ 4.94; Fingernails > Toenails
  • Most common nail plate changes: onychorrhexis (100%), longitudinal melanonychia (88.9%), onychoschizia (82.2%), thinning and distal splitting (62.2% and 48.9%)
  • Most common nail fold changes: ragged cuticle (91.1%), absent cuticle (11.1%), nail fold hyperpigmentation (11.1%)
  • Most common nail bed changes: erythema (88.9%), onycholysis (55.5%), subungual hyperkeratosis (46.7%)
  • Histopath:
    • Major criteria – 51.1%
      • Sawtooth acanthosis – 44.4%
      • Lymphocytic infiltrate – lichenoid band under the dermo-epidermal junction – 24.2%
    • Minor criteria
      • Most common: presence of granular layer in nail matrix and bed epithelium – 51.1%
      • Increased eosinophilia of nail bed keratinocytes – was not seen in any
    • Additional significant finding: “frayed nail plate” due to separation of individual orthokeratotic onychocytes from the nail plate – seen in 33.3% of cases – not previously reported in other studies (see image below)

Most memorable tweets and few pearls from the article’s discussion:

  • Mean age of nail involvement with LP was lower than previously stated – possibly related to increased awareness of cosmetic appearance of nails
  • Mucosal LP was the most common association with nail LP – Dr Rubin also accounts for this association in his nail clinic as well
  • Most common nail fold involvement: ragged cuticle – 95.5%

And now a SPECIAL TREAT for all of you, a SPECIAL interview with Dr Adam I. Rubin (@adamirubin) on the ASDP YouTube channel: Dr Jisun Cha and Dr Gottesman’s #DermpathJC Q&A session with Dr Adam Rubin about lichen planus of the nail unit. While much of the video focuses on the histopathologic features of nail lichen planus and its mimics, the last 15minutes of the discussion are focused on various treatment options for this disease.

Until next month #dermpathJC, stay safe!

#dermpathJC November/December 2020 summary

#dermpathJC November/December 2020:

Thursday, December 10th, 9pm EST

Article Discussed: Concordance Analysis of the 23-Gene Expression Signature (myPath Melanoma) With Fluorescence In Situ Hybridization Assay and Single Nucleotide Polymorphism Array in the Analysis of Challenging Melanocytic Lesions: Results From an Academic Medical Center

Authors: Stephanie A. Castillo, MD, Anh K. Pham, MD, Alicia T. Dagrosa, MD, MBA, Shaofeng Yan, MD, PhD, Dorthea T. Barton, MD, Joel A. Lefferts, PhD, and Konstantinos Linos, MD

Temporary free access courtesy of The American Journal of Dermatopathology: DOI: 10.1097/DAD.0000000000001713

Summary prepared by: Anthony Wheeler, MD (@Pathosomes)

Journal Club Summary:

  • This article reviewed concordance between molecular tests used to assist in the diagnosis of challenging melanocytic lesions
  • Histology is the gold standard for diagnosing melanoma and other melanocytic lesions
  • At times the histologic interpretation of the specimen may be particularly challenging, thus it may be prudent to obtain molecular testing
  • The molecular tests that were assessed include fluorescence in situ hybridization (FISH), single nucleotide polymorphism (SNP) arrays, and 23-gene expression signature (GES)
  • FISH molecular testing uses specific DNA probes that can bind to a region of interest on a particular chromosome. There are various different DNA probes that can detect repetitive sequences, missing sequences, there are also whole chromosome probes, telomeres probes, chromosome breaks and fusion probes.
  • Chromosomal abnormalities due to copy number differences have been reported in melanoma, such as gains in 6p25 (RREB1) and gains in RREB1/Cep6, losses in 6q23 (MYB), gains in 11q13 (CCND1), gains in 8q24 (MYC), and mutations in 9q21 (CDKN2A) gene.
  • A CME article from the American Journal of Dermatopathology by Ferrara et al (doi: 10.1097/DAD.0000000000000380) summarizes that “melanoma commonly harbor gains at 6p, 7q, 17q, 20q, 4q, 8q, 1q, and 11q, whereas common deletions include 9p, 10, and 21q. In particular, 6p gain in melanoma was associated with an unfavorable prognosis.”
  • SNPs can be used to detect small copy number variations. They can be interpreted as normal if there is no deviation in the copy numbers, equivocal if there is low number of copy number aberrations and abnormal if there are multiple complex aberrations or if there are gains or losses in chromosomes 1, 6, 8, 9, and 11. To add, if 11p gain (HRAS) is the only abnormality detected in a specimen with spitzoid morphology, the authors share that this was deemed benign because this is an expected finding in some Spitz nevi.
  • The 23-GES utilizes qRT-PCR to detect expression of twenty three genes to help distinguish melanoma from melanocytic nevi. myPath® Melanoma is a 23-gene expression signature (GES) test and categorize lesions as benign, malignant, or indeterminate.
  • FISH, SNP, and GES have all been shown to aid in the diagnosis of challenging melanocytic lesions
  • The American Society of Dermatopathology Appropriate Use Criteria Task Force recognizes the use of FISH and SNP testing to assist in the diagnosis of challenging melanocytic lesions
  • The researchers utilized their experience with the GES assay to primarily investigate the degree of concordance between GES and FISH, as well as GES and SNP
  • The researchers utilized a single-institution retrospective analysis of 61 contiguous cases of challenging melanocytic lesions that required molecular analysis
  • The primary objective of the study was to determine the interest agreement between GES and FISH, and the interest agreement between GES and SNP arrays in the analysis of challenging melanocytic lesions
  • A secondary objective was to determine the combined test performance between the molecular tests that were utilized
  • The specimens that were included in the study were not metastatic, or re-excisions, and had at least two molecular tests
  • SNP array cases with a spitzoid histomorphology and a sole 11p gain abnormality were considered benign, due to the consistency of these findings being diagnostic of Spitz Nevi
  • Cases that underwent 23-GES (myPath® Melanoma) testing involved sending unstained slides and an hematoxylin and eosin (H&E) slide with the lesion marked to Myriad Genetics, where the specimen was assessed and proprietary scored
  • SNP analysis was performed at the researchers home institution by extracting DNA from a formalin fixed paraffin-embedded specimen, and utilizing the OncoScan FFPE Assay Kit (Affymetrix, Inc., Santa Clara, CA)
  • FISH analysis for many of the specimens was performed at the Mayo Clinic Laboratory utilizing a marked H&E slide to locate the lesion as a reference, to guide location for hybridization on the unstained slides using specific probes for melanoma. Two technologists analized a total of 50 interphase nuclei for each probe (25 nuclei each).
  • The overall percent agreement between GES and FISH was 50.9%, and the percent agreement between GES and SNP was 57.1%
  • Percent agreement was improved, when indeterminate/equivocal results were excluded, to 69.7% (for GES and FISH), to 77.8% (for GES and SNP).
  • The combined-test analysis supports the utilization of more than one molecular test to increase the odds of obtaining a successful test on challenging melanocytic lesions
  • Perhaps in the future an ideal concordance study can be done and include lesions that have had three different molecular tests

Memorable Tweets From The Interesting Discussion:  

Until next month #dermpathJC, stay safe!

#dermpathJC October 2020 summary

#dermpathJC October 2020:

Thursday, October 29th, 9pm EST

Article Discussed: A review of CD30 expression in cutaneous neoplasms

Authors: Drs. Franziska Kampa and Christina Mitteldorf

Temporary free access courtesy of Journal of Cutaneous Pathology, link: https://onlinelibrary.wiley.com/doi/abs/10.1111/cup.13894

Summary prepared by: Maryam Aghighi, MD (@maryam_aghighi)

Editor: Silvija P. Gottesman, MD (@SGottesmanMD)

Journal Club Summary:

  • The current article reviewed the literature for CD30 expression in lymphoproliferative disorders and solid tumors of the skin.
  • CD30 (Ki-1) is a transmembrane protein in the tumor necrosis factor receptor superfamily. It is expressed by Reed-Steinberg cells. The CD30 ligand (cytokine) is detected on activated lymphocytes, histiocytes and granulocytes.
  • CD30 is expressed mainly on Th2 cells, but there is some published data that Th0 and Th1 cells show CD30 expression. As for B-cells, CD30 is expressed in B-cell immunoblasts, found at the germinal center periphery.
  • CD30 is expressed in anaplastic large cell lymphoma (ALCL), Hodgkin lymphoma (HL), lymphomatoid papulosis (LyP), mycosis fungoides (MF), follicle center cell lymphoma (FCL) and Epstein-Barr virus (EBV)-associated lymphomas.
  • Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody, conjugated with monomethylauristatin, and used in the treatment of CD30+ HL, systemic ALCL, CD30 expressing peripheral T-cell lymphomas and CD30+ cutaneous T-cell lymphomas.
  • Treatment with BV has been effective in cutaneous T-cell lymphomas (CTCL) and diffuse large B-cell lymphoma (DLBCL) including in cases with low or absent CD30 expression.
  • In cutaneous lymphomas, the CD30 positivity threshold is under debate. Up to 40% of hematopathologists use a positive cut-off value of >20% CD30+ cells, while the response cutoff in BV clinical trials was >10% CD30+.
  • Cutaneous and folliculotropic MF patients with a higher dermal CD30 expression showed a more advanced stage at diagnosis, higher maximum stage, lower survival rate and poor prognosis. However, patients with high epidermal CD30 expression revealed higher survival rate.
  • Transformed MF (T-MF) is diagnosed if >25% large cells (>4x the size of a lymphocyte) are present. Dermal CD30 expression is related to a better prognosis in T-MF and absence of CD30 expression was associated with poorer prognosis. Interestingly, higher epidermal CD30 expression compared to dermal CD30 expression was associated with a poorer survival.
  • In other rare types of CTCLs, published literature to date of CD30 expression is as follows:
    • In pagetoid reticulosis (PR), more than 50% of the tumor cells were CD30+.
    • Primary cutaneous peripheral T-cell lymphoma, not otherwise specified (pcPTCL-NOS) reported CD30 expression as follows:
      • One study showed low expression of CD30 (<5%) in most of their patients.
      • One study showed more than half the studied patients to have a CD30 expression of 25% or more.
      • In small-medium pleomorphic T-cell lymphoma (SMPTCL) CD30-positive expression was reported between <1% and 30%.
    • In cases of extranodal NK/T-cell-lymphoma (ENK/TCL), CD30 positivity has been seen and in one case reaching >80%.
    • Primary cutaneous gamma-delta T-cell lymphoma (pcGD-TCL), primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECTCL) and subcutaneous panniculitis-like T-cell Lymphoma (SPTL) reported CD30 expression (further reading recommended to explore the amount of CD30 expression in each of these distinct entities).
    • A single case of primary cutaneous acral CD8+ T-cell lymphoma (pcATCL) reported negative CD30 expression.
    • Adult T-cell leukemia/lymphoma (ATLL) reported positive CD30 expression but skin expression of CD30 positivity was not mentioned.
  • Observed CD30 expression in primary cutaneous B-cell lymphomas is as follows:
    • Primary cutaneous follicle center B-cell lymphomas with CD30 expression was seen in few patients and primary cutaneous marginal zone B-cell lymphoma showing CD30 positivity was seen in even fewer patients.
    • Four diffuse large B-cell lymphoma leg type patients reported negative CD30 staining.
  • EDV-positive mucocutaneous ulcer and EDV-associated lymphoproliferative disorders reported high CD30 expression.
  • Blastic plasmacytoid dendritic cell neoplasm – negative CD30 expression reported thus far.
  • Cutaneous mastocytosis had CD30 expression in 96.5% of cases (29 study patients).
  • Other notable neoplasms that also showed expression of CD30 were lymphadenomas. CD30 expression was reported in the the tumor microenvironment (TME) of BCC, SCC and keratoacanthomas.
  • There was no data reported regarding CD30 expression in Merkel cell carcinoma and only a couple of cases of atypical fibroxanthoma with reported CD30 expression.  

Memorable Tweets from the Journal Club Discussion:

Until next month #dermpathJC, stay safe!

#dermpathJC September 2020 summary

#dermpathJC September 2020:

Thursday, September 24th, 9 pm EST

Article Discussed: Pityriasis Lichenoides: a large histopathological case series with a focus on adnexotropism

Authors: Menzinger, Sébastien MD, Frassati-Biaggi, Annonciade MD, Leclerc-Mercier, Stéphanie MD, Bodemer, Christine MD, PhD, Molina, Thierry Jo MD, PhD, Fraitag, Sylvie MD

Temporary free access courtesy of American Journal of Dermatopathology: https://doi.org/10.1111/cup.13585

Summary prepared by: Riddhish Sheth, MD (@RShethMD)

Journal Club Summary:

Pityriases lichenoides (PL) is a rare skin disorder, the acute form of which is predominantly seen in children and young adults (PLEVA – pityriasis lichenoides et varioliformis acuta) and a milder, more chronic form (PLC – pityriasis lichenoies chronica), more often seen in adults. There is also a severe form known as febrile ulceronecrotic Mucha-Habermann disease. 

PLEVA histologically presents with epidermal hyperplasia with parakeratosis and neutrophils in the stratum corneum, dyskeratotic keratinocytes, interface dermatitis, lymphocytic exocytosis, dermal perivascular lymphocytic infiltrate, and red blood cell (RBC) extravasation.  PLC is described to have much milder changes.  There are cases where the histological features are incomplete or lack specificity which can lead to misdiagnosis of a lymphoproliferative disorder such as Lymphomatoid Papulosis (LyP).

71 cases were investigated in this case series. The authors noticed that vacuolated, necrotic keratinocytes were present in all cases, superficial and deep lymphocytic infiltration was present in 99% of cases, and adnexal lymphocytic infiltration was present in 97% of cases.  They noted that the inflammatory cells were mostly lymphocytes, neutrophils were only present in cases with ulceration of the superficial dermis, and that there were no eosinophils histologically identified in any of the study’s cases.  The authors also noted that 83% of cases showed perivascular or intraepidermal RBCs, and that 42% of cases had pallor of the upper part of the epidermis.  The authors alluded to Dr. Ackerman and his description of Pityriasis Lichenoides which included the superficial epidermal pallor but stated that this sign was not always easy for them to evaluate because it may be technique dependent.    

Immunohistochemical (IHC) studies were also performed on 11 cases at random and there was no IHC staining profile pattern which they found that would be reliable to aid in the diagnosis of the Pityriasis Lichenoides.

To go back to the adnexotropism mentioned earlier, the authors conclude that the superficial and deep dermal lymphocytic infiltrate is arranged in a periadnexal manner and it manifests as a “T-shaped” infiltrate which can be a low power clue in the diagnosis of Pityriasis Lichenoides.  They compared this low power pattern of the lymphocytic infiltrate to Vachellia tortilis, an African thorn acacia tree. This was seen in 97% of the cases in this series. 

Vasculitis or eosinophilic infiltrates are not a feature of Pityriasis Lichenoides.  Furthermore, in this case series, there were no histologic differences present between the specimens of adults and children.

Memorable Tweets:

Until next month #dermpathJC, stay safe and stay curious!

#dermpathJC August 2020 summary

#dermpathJC August 2020:

Thursday, August 27th, 9 pm EST

Article Discussed: Diffuse dermal angiomatosis associated with calciphylaxis: A 5‐year retrospective institutional review

Authors: Heather M. O’Connor, Qiong Wu, Steven D. Lauzon, Jessica A. Forcucci

Temporary free access courtesy of Journal of Cutaneous Pathology: https://doi.org/10.1111/cup.13585

Summary prepared by: Stanton Miller, MD (@StanMiller17)

Editor: Silvija P. Gottesman, MD (@SGottesmanMD)

Journal Club Summary:

Diffuse dermal angiomatosis (DDA) is a rare cutaneous vascular disorder, which was first reported by Krell et al. in 1994. It presents with violaceous plaques on the lower legs or affects pendulous breasts and it frequently ulcerates. Contributing factors are smoking, anticardiolipin antibodies and atherosclerosis. Associated conditions are cutis marmorata telangiectatica congenita and calciphylaxis, the latter being an inspiration for the study.

Histologic findings of Diffuse dermal angiomatosis show a vascular proliferation in the superficial and reticular dermis devoid of atypia and significant amount of inflammation. Vascular immunohistochemical markers can be used to highlight the extent of the proliferation.

  • The aim of the study was to investigate any association between calciphylaxis and diffuse dermal angiomatosis (DDA). There are some theories that DDA is a reactive vascular proliferation secondary to local ischemia and local production of vascular endothelial growth factor.
  • Calciphylaxis is associated with end-stage renal disease (elevated levels of calcium and phosphate). Patients with non-uremic calciphylaxis usually have either obesity, liver disease, hypercoagulability, use of warfarin or systemic steroids or autoimmune diseases. Histologically, deposition of calcium within small vessel walls of the subcutis is seen.
  • The authors noticed that some calciphylaxis biopsies have evidence of DDA in the overlying dermis and that it can be used as a helpful clue to dissect deeper in the fat and look for any evidence of small vessel obstruction by calcium.
  • The study showed statistically significant relationship between DDA and African-American race and Chronic Heart Failure. This is newly reported information in the literature. Patients with calciphylaxis and CHF had 33.2 times the odds of having associated DDA in their biopsies compared to those without CHF, and African-Americans with calciphylaxis had 22.2 times the odds of having associated DDA in their biopsies as compared to Caucasians.
  • End-stage renal failure, diabetes mellitus, immunosuppressive or hypercoagulable states, arrhythmias, Body Mass Index, hypertension, coronary artery disease, age, duration of calciphylaxis symptoms, and gender were NOT found to have statistically significant associations.

Memorable tweets:

  • There is a histologic distinction between DDA and Reactive angioendotheliomatosis and whenever possible the correct entity should be used in signout.
  • Communication between the pathologist and the clinician remains of paramount importance.

Take home point:

  • While Diffuse dermal angiomatosis has been seen in some cases of calciphylaxis, the most common scenario among the dermatopathologists have been of a benign vascular proliferation involving pendulous breasts. Always consider clinical presentation and location when making the diagnosis.

Until next month #dermpathJC, stay safe!

#dermpathJC June 2020 summary

#dermpathJC June 2020:

Thursday, June 25th, 9 pm EST

Articles discussed:

#1: Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of 5 cases

  • Authors: Cynthia Magro, J. Justin Mulvey, David Berlin, Gerard Nuovo, Steven Salvatore, Joanna Harp, Amelia Baxter-Stoltzfus, Jeffrey Laurence

#2: Skin manifestations of COVID-19

  • Authors: Sarah Young, MD, Anthony P. Fernandez, MD, PhD

#3: Thrombotic occlusive vasculopathy in a skin biopsy from a livedoid lesion of a patient with COVID-19

  • Authors: M. Llamas-Velasco, P. Muñoz-Hernández, J. Lázaro-González, A. Reolid-Pérez, B. Abad-Santamaría, J. Fraga, E. Daudén-Tello

#4-1: Digitate Papulosquamous Eruption Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection/#4-2: Petechial Skin Rash Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection

  • #4-1 Authors: Adrien Sanchez, Pierre Sohier, Sarah Benghanem, Anne-Sophie L’Honneur, Flore Rozenberg, Nicolas Dupin, Bethsabée Garel
  • #4-2 Authors: Borja Diaz-Guimaraens, MD, Miguel Dominguez-Santas, MD, Ana Suarez-Valle, MD, Cristina Pindado-Ortega, MD, Gerald Selda-Enriquez, MD, Sonia Bea-Ardebol, MD, Diego Fernandez-Nieto

#5: Chilblains in children in the setting of COVID-19 pandemic

  • Authors: David Andina MD, Lucero Noguera-Morel MD, Marta Bascuas-Arribas MD, Jara Gaitero-Tristán MD, Jose Antonio Alonso-Cadenas MD, Silvia Escalada-Pellitero MD, Ángela Hernández-Martín MD, Mercedes de la Torre-Espi MD, Isabel Colmenero MD, Antonio Torrelo MD

#6: Histopathological Study of a Broad Spectrum of Skin Dermatoses in Patients Affected or Highly Suspected of Infection by COVID-19 in the Northern Part of Italy: Analysis of the Many Faces of the Viral-Induced Skin Diseases in Previous and New Reported Cases

  • This article was not discussed during journal club but is recently published and included in the below summary
  • Authors: Raffaele Gianotti, MD, Sebastiano Recalcati, MD, Fabrizio Fantini, MD, Cristina Riva, MD, Mario Milani MD, Emanuele Dainese, MD, and Francesca Boggio, MD

All articles are open access with freely accessible histologic images.

Summary prepared by: Suzy Bloomquist, MD (@BloomquistSuzy)

Article summary:

The June 2020 DermpathJC covered a variety of articles on a new topic relevant to the ongoing pandemic – COVID-19-related skin conditions, including the clinical presentations and varied histologic appearance of the eruptions. Articles on this topic are limited to case presentations and case series; however many dermatopathologists are beginning to see these lesions in their clinical practice, highlighting the importance of sharing our knowledge on these topics. The various articles present a spectrum of the possible histologic patterns present in skin lesions of COVID-19 positive (or suspected positive) cases. Participating dermatopathologists added to the discussion with their experience regarding similar cases.

Introduction:

  • Skin manifestations are well known in the setting of viral illnesses. Some authors have reported skin involvement more than 20% of COVID-19 positive patients.
  • We are at a relatively early stage in the description of skin lesions relating to COVID-19. Even at this early stage however it appears that COVID-19 may have unique skin manifestations when compared with other viral illnesses. Further study is needed to determine the true specificity of these skin lesions.
  • The picture of cutaneous manifestations of COVID-19 is complicated by the fact that many patients are severely ill and being treated with medications at the time of biopsy; some of the cutaneous lesions may overlap with drug adverse effects.
  • There are still relatively few articles detailing histologic descriptions of COVID-19-related skin lesions in patients seen in the outpatient setting and in hospitalized patients.

Summary of clinical presentations of COVID-19-related skin disease:

  • Highly variable among patients and a single patient may present with multiple simultaneous cutaneous lesions of varying morphologies.
  • Many presentations including:
    • Lesions that are more non-specific:
      • Exanthematous/morbilliform rash
      • Urticarial
      • Maculopapular
      • Petechial rash
      • Pityriasis-like digitate papulosquamous eruption
      • Erythema-multiforme like lesions
      • SDRIFE-like eruption
      • Others (a single patient exhibiting multiple different
    • Lesions that may be more specific/unique to COVID-19:
      • Acral perniosis/Chilblains (“COVID toes”) – despite the descriptor may be seen on fingers and toes, consists of acral erythemato-violaceous or purpuric macules with some cases showing dark ischemic areas with superficial blisters or swelling.
      • Livedoid/retiform purpuric/vasculopathic lesions – these seem to be seen more frequently in cases of severe illness/acute respiratory failure in our chosen articles.
      • Varicella-like vesicular eruptions

Summary of histologic descriptions of biopsied lesions:

  • Retiform purpuric/livedoid lesions: thrombogenic vasculopathy at all levels of biopsy (including deep dermis) seen in either (or both) arteries or veins, accompanied in some cases by extensive necrosis of epidermis and adnexal structures, interstitial and perivascular neutrophil or lymphocytic infiltrate, prominent leukocytoclasia (one study noted deposition of C5b-9 in vessels in these cases with biopsy of normal skin in these patients also showing this deposition)
  • Perniosis/chilblains lesions on acral skin (largest study is in children/adolescents):  vacuolar degeneration of basal layer and lymphocytic exocytosis, perivascular (in-some cases dense/sleeve-like) and perieccrine lymphocytic infiltrate (prevalence of cytotoxic CD8+ lymphocytes), lymphocytic vasculopathy, acrosyringium, eosinophils in eccrine glands, microthrombi in small dermal vessels, scattered necrotic keratinocytes in one case, acute edema and severe vascular damage in cases of large bulla
  • Vesicular eruptions: interface dermatitis with apoptotic keratinocytes (similar to findings in other viral exanthems).
  • Exanthematous and maculopapular (non-specific) lesions:
    • Summarization of findings: Dermal edema, dilated capillaries, prominent erythrocyte extravasation, lymphohistiocytic infiltrate which may be perivascular, dilated vessels
    • Few cases also showed: spongiosis, minimal vacuolar dermal-epidermal junction changes, erythrocyte extravasation, eosinophils, nests of intraepidermal Langerhans cells.
  • Other: acantholytic dermatitis resembling Grover disease (2 cases)

Short review of chilblains/pernio:

  • A cutaneous localized inflammatory reaction resulting from maladaptive vascular response to non-freezing cold. Classified as primary or secondary to underlying disease. None of the cases of chilblains in suspected COVID-19 patients had other potential etiologies for chilblains. Chilblains in these cases should not be confused with the more thrombotic/livedoid complications observed in severely ill patients with COVID-19 (described more thoroughly in articles 1,3).

What can we learn from the skin of COVID-19 patients to infer its effect on other organs?

  • It seems clear that SARS-CoV-2 travels rapidly through the vascular system via an unknown mechanism. Some theories behind this are activation of eosinophils leading to a prothrombotic state or activation of a mannose-binding lectin pathway via glycoprotein binding and direct interaction with endothelium.

Additional points:

  • Deposition of C5b-9 was seen within dermal capillaries of even normal appearing skin of suspected COVID-19 positive patients in one study.
  • Article #2 highlighted that medications being used to treat COVID-19 also have cutaneous adverse reactions.
  • Little is known regarding the clinical value of recognition of cutaneous manifestations – for example, are there early cutaneous signs that may suggest a COVID-19 infection?
  • RT-PCR was performed on fresh skin in study #4 and was negative for SARS-CoV-2
  • The patient in article #4 had resolution of their rash within one week although the patient subsequently died of COVID-19-related illness.
  • In article #5, all adolescent/pediatric patients with chilblains had an excellent outcome without complications or severe disease manifestations with symptoms beginning to fade after 7-10 days.

A very important caveat:

  • Not all of the lesions described in these articles were in patients confirmed to have COVID-19, many were suspected cases. In study #5, while in the majority of cases (59%) a history of close contact with a COVID-19 symptomatic adult was noted, only 1 of 19 tested patients was PCR positive (however the study notes that PCR is positive in only 11.2% of children requiring hospital admission for suspected COVID-19).

In sum, there’s much to be learned about COVID19 #dermpath. We are grateful for open communications between dermatologists and pathologists, as clinicopathologic correlation is of paramount importance during these times.

Until our next journal club, be well and stay safe,

Sincerely,

DermpathJC

#dermpathJC May 2020 summary

#dermpathJC May 2020:

Thursday, May 28th, 9 pm EST

Article discussed: Pleomorphic dermal sarcoma: a more aggressive neoplasm than previously estimated

Authors: Juan C. Tardío, Fernando Pinedo, José A. Aramburu, Dolores Suárez-Massa, Ana Pampín, Luis Requena and Carlos Santonja

Temporary open access courtesy of Journal of Cutaneous Pathology: https://doi.org/10.1111/cup.12603

Summary prepared by: Cacey Peters, M.D. (@caceypeters)

Article Summary:

Pleomorphic dermal sarcoma (PDS) is a rare neoplasm similar to atypical fibroxanthoma, but has fetaures of tumor necrosis, invasion beyond superficial subcutis or vascular or perineural infiltration. Metastatic risk is less than 5%, but ultimately very rare and more studies are needed to ascertain exact risk. The neoplasm fails to show any staining for cytokeratins, S100 protein, desmin or CD34.

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Journal Club Summary:

  • Atypical fibroxanthoma (AFX) is most commonly found on sun-exposed skin of the elderly, particularly the head
  • Histologically characterized by a mixture of spindle, epithelioid, and multinucleated giant cells with marked pleomorphism and many mitoses
  • Architecture may be fascicular, storiform, or haphazard
  • Immunohistochemistry is negative for cytokeratins (CK), S100, desmin, and CD34 while positive for vimentin, CD10, CD99 and variably CD68 and p53
  • 42, a marker of normal and neoplastic follicular dendritic cells (FDC), was shown to be positive in 50% of cases in this study and were negative for other FDC markers such as CD21 and CD23
    • Unfortunately, CNA.42 is positive in AFX, leiomyosarcomas, melanomas and carcinomas (unpublished observations by the authors)
  • According to the WHO, necrosis, invasion into deep subcutis or underlying fascia or skeletal muscle, lymphovascular invasion, or perineural invasion do not constitute a diagnosis of AFX
  • The name “pleomorphic dermal sarcoma” (PDS) has been proposed for such lesions, formally known as cutaneous malignant fibrous histiocytoma (MFH)
  • Confusion has ensued due to the lack of understanding about the true behavior of these lesions as well as some use of both terms as synonyms in the literature
  • Although controversy exists about using different terms for naming members of the same disease spectrum, the differences in clinical behavior between AFX and PDS merits an unambiguous message to the clinicians that is better guaranteed, in the authors opinion, distinguishing them by nomenclature
  • Clinical behavior is indolent with rare recurrence and even rarer metastasis (5% based on limited data and classification criteria)
  • Combining data from this study and a previous study by Miller et al, PDS seems to have a more aggressive clinical behavior, estimated to be 14% metastasis rate, including the skin, regional lymph nodes, and the lungs
  • At least 3 patients died from PDS (7%)
  • When metastasis has occurred, some cases infiltrate beyond the subcutis, contain necrosis, or contained no histopathologic or immunohistochemical information
  • A diagnosis of PDS should be reserved for tumors in sun-damaged skin of the elderly because they are extremely rare in non-sun-damaged skin, if they exist at all
  • TERT promoter mutations with an ultraviolet signature in 76% of PDS supports this view
  • Deletions in chromosomes 9p and 13p are seen in PDS at a similar frequency as AFX and undifferentiated pleomorphic sarcomas (UPS)
  • UPS shows H-ras and K-ras mutations (absent in AFX) and overall, more genetic alterations in complete genomic hybridization (CGH) studies
  • The authors retrospectively studied 18 PDS with emphasis on outcome and the differential diagnosis
  • Out of 12 previously classified PDS/cutaneous MFH and 112 AFX, the inclusion criteria for the series were as follows:
    • Spindle cell and/or pleomorphic dermal-based mesenchymal neoplasms without morphologic or immunohistochemical features diagnostic of any distinct entity
    • Lack of CK, S100 protein, desmin and CD34 expression
    • Invasion of at least the deep subcutis and/or tumor necrosis and/or vascular or perineural infiltration
  • 9 of the 12 PDS were excluded because primary subcutaneous sarcoma infiltration into the dermis could not be ruled out and expression of one or more of the above IHC
  • 15 of the 112 AFX cases were reclassified as PDS making a total of 18 PDS
  • M:F ratio was 1:1 (in contrast to previously reported male predominance)
  • Mean age was 81
  • Patients either had prior trauma or carcinomas in the same vicinity or immunosuppression due to rheumatoid arthritis, renal disease, or their age
  • Clinically they were described as either plaques or tumors, 10 of which were ulcerated
  • Mean size was 22mm with a range from 7-70mm
  • 13 cases showed an asymmetric silhouette and 15 cases showed an infiltrative border
  • Grenz zone, epidermal collarette and epidermal connection were absent in all cases
  • Except in cases with a conventional carcinomatous, melanocytic or sarcomatous component, sarcomatoid carcinoma, melanoma, leiomyosarcoma and angiosarcoma are mainly differentiated from PDS by their immunohistochemical (IHC) features
  • Sarcomatoid carcinoma will stain for cytokeratins, especially high molecular weight, and also p63 and EMA but can also be seen in PDS which makes them less useful
  • There will usually be numerous S100+ dendritic cells in PDS but never the neoplastic cells which helps differentiate PDS from melanoma, which will also likely have a conventional or in situ component
  • Leiomyosarcoma will have desmin and smooth muscle histologic features with marginated fascicles and characteristic elongated blunt-ended nuclei with fibrillary cytoplasm
  • Angiosarcoma has a similar site predilection to PDS, hemorrhage, and is positive for CD31, but is also positive for CD34 and ERG as well as a different clinical appearance with large ill-defined bluish, bruise-like patches that evolve into elevated plaques
  • Dermatofibrosarcoma protuberans (DFSP) is more common in younger patients on the trunk or proximal extremities and has a lace-like pattern that can mimic PDS along with CD34 positivity, however, DFSP has uniform spindle cells arranged in a monotonous storiform pattern somewhere within the lesion, even if there are MFH areas with loss of CD34, that will aid in the diagnosis of DFSP
  • Atypical and cellular dermal fibrous histiocytomas can have spindle to pleomorphic areas that may resemble PDS with similar lack of specific IHC, but usually present on the extremities of young to middle-aged adults with a Grenz zone and peripheral collagen entrapment that is limited to the dermis or, at most, the superficial subcutis
  • If PDS contains myxoid stroma, these must be distinguished from myxofibrosarcoma which differ in that they are often on the extremities, have a multinodular growth patter, broad spectrum of celluarity to stroma ratio, characteristic curvilinear thin-walled vessels and pseudolipoblasts.

Memorable tweets:

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Until next month #dermpathJC, stay safe!

#dermpathJC April 2020 summary

#dermpathJC April 2020:

Thursday, April 30th, 9 pm EST

Article discussed: Cutaneous carcinosarcoma: a series of six cases and a review of the literature

Authors: Joshua J. Clark, Anneli R. Bowen, Glen M. Bowen, John R. Hyngstrom, Michael L. Hadley, Keith Duffy, Scott R. Florell and David A. Wada

Open access courtesy of Journal of Cutaneous Pathology: https://onlinelibrary.wiley.com/doi/epdf/10.1111/cup.12843

Summary prepared by: Cacey Peters, M.D. (@caceypeters)

 

Journal Club Summary:

  • Coined by Virchow in 1864, the term carcinosarcoma refers to a biphasic malignant neoplasm with epithelial and mesenchymal components which can be seen in virtually every organ
  • In primary cutaneous carcinosarcoma, the most common epithelial components are basal cell and squamous cell carcinomas, whereas the less common include malignant spiradenoma, porocarcinoma, pilomatrical carcinoma, and trichoblastic carcinoma
  • The mesenchymal component includes fibrosarcoma, pleomorphic undifferentiated sarcoma (previously called malignant fibrous histiocytoma), osteosarcoma, chondrosarcoma, and rhabdomyosarcoma
  • Although cutaneous carcinosarcomas are rare, they are likely under-reported due to lack of awareness, tissue sampling variation, and the variety of clinical/histological phenotypes
  • Of the reported cases reviewed, most occurred on sun-exposed areas of the head and extremities with age ranges from 32 to 98 years old, most cases occurring in the 8th and 9th decades of life
  • Male predominance was found to be 1.7:1
  • Recurrence and death were more common from adnexal carcinosarcomas with equal distribution among the various adnexal groups
  • Patients with basal cell carcinosarcoma had longer disease-free survival than those with squamous cell carcinosarcoma
  • The two hypotheses of the origin of carcinosarcoma include a monoclonal carcinoma that undergoes metaplasia with loss of residual epithelial differentiation versus a convergence of two or more distinct progenitor cells
  • Multiple molecular studies of non-cutaneous carcinosarcomas favor a monoclonal cell population with differentiation into both epithelial and mesenchymal components
  • Basal cell carcinosarcoma has been shown to be related to sun damage with mutations in PTCH1, p53, p63, and p13 genes
  • Squamous cell carcinosarcoma has been shown to have point mutations and deletions in the TP53 gene
  • The main histologic differential diagnosis of malignant biphasic neoplasms includes sarcomatoid carcinoma, malignant mixed tumor, biphasic synovial sarcoma, and malignant peripheral nerve sheath tumor
    • Sarcomatoid carcinoma (spindle-cell squamous carcinoma) = malignant spindle cells with some degree of typical squamous cell carcinoma which can be proven with immunohistochemistry (IHC) for keratins and/or p63 by the spindle cells
    • Biphasic synovial sarcoma = uncertain histogenesis; extremities; young adults; epithelial cells in cords/nests/glands with admixed cellular, monotonous spindle cell proliferation; confirmed with TLE1, EMA, and/or cytokeratin as well as t(X;18) translocation
    • Malignant mixed tumors of the skin = contain carcinoma admixed with benign myxoid or chondroid proliferations; may be S100+
    • Malignant peripheral nerve sheath tumor (MPNST) = rarely can have mucin-producing glands with cuboidal/columnar cells admixed with malignant spindle cells that otherwise fits criteria for the typical MPNST
  • Three diagnostic criteria have been proposed for primary cutaneous carcinosarcoma
    • Clearly defined dual neoplasm with explicit characterization via histology and IHCs
    • Exclusion of metastasis from other sites
    • Exclusion of sarcomatous stromal changes around otherwise normal stroma of a carcinoma
  • There is a lack of criteria to differentiate squamous cell carcinoma with sarcomatoid differentiation from cutaneous carcinosarcoma
  • Management of cutaneous carcinosarcoma depends on the clinical and histologic features
    • The epithelial component correlates with metastasis
      • Basal cell carcinosarcoma = low-risk (2%)
      • Squamous carcinosarcoma and adnexal carcinosarcoma = (12-50%)
    • Tumor size, recent growth, metastases, and tumor chronicity may also affect management but are limited in number for definitive recommendations

Memorable Tweets:

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Until next month #dermpathJC, stay safe!