NORTH CAROLINA DERMATOLOGY ASSOCIATION
2017 SUMMER MEETING
This continuing medical education activity is jointly provided by theNorth Carolina Dermatology Association and
Southern Regional Area Health Education Center SUNDAY HANDOUTS
JULY 7-9, 2017 | OMNI HOMESTEAD RESORT | HOT SPRINGS, VIRGINIA
1
ARTIFICIAL INTELLIGENCE AND MELANOMA
DIAGNOSIS :AM I OUT OFA JOB?
.
Kelly Nelson, MD FAAD
Associate Professor
Department of Dermatology
MDAndersonCancerCenter
http://mdacc.participoll.com
•Noconflicts
Access Seeing it
Melanoma Secondary Prevention
Diagnosticaccuracy
2
Seeing itAccess
Diagnosticaccuracy
Melanoma Secondary Prevention
Dermoscopy
Lancet Oncol 2002;3(3):159‐65; PMID11902502
Dermli e-oto IIPro Plus wi h
ikonD500
$3,995 00
Dermli e Cam®
$2,195.00
Dermli e Foto II Pro
$199500Dermu-e FOTO Sys em
$1 995.00
Dermu e -oroS1150 00
Dermli eDL1
$495 00Dermli e o_1 basic
$299 95
Dermli e Oo iPhone 5/SS
Adapter
$39 00
ikon 1 AW1 with
Mag e iConnect®
$895 00
)
Sony cybersho- DSC-W800 20.1
Dermlite rlOD
$79 95
Dermlite riOD iPhone 6/6S
Adapter
$39 00
3
Automated dermoscopic analysis
MelaFind
Automatedmultispectraldermoscopy analysis
FDAapproved
Expensive
Sn 98.4, Sp9.9
Arch Dermatol 2011;147:188. PMID 20956633
Other diagnostic technologies
• Reflectance confocalmicroscopy
• Optical coherence tomography
• High frequency ultrasound
• Tape stripping
• Spectroscopy
■ Expensive
■ Bulkymachines
■ Challenging imageacquisition
■ True predictive capacity
0A B
Have your patients asked you about this?
A: yes
B: no
Nature. 2017 Feb 2;542(7639):115‐118; PMID 28117445
4
Artificial Intelligence and Image Recognition• Feature extraction +Classification
• Deep Convolutional NeuralNetwork• Overlapping data intake fields
• Convolutional processing
• Deep learning
• GoogleNet Inception v3 CNNarchitecture
Nature. 2017 Feb 2;542(7639):115‐118; PMID 28117445
Nature. 2017 Feb 2;542(7639):115‐118; PMID 28117445
5
Nature. 2017 Feb 2;542(7639):115‐118; PMID 28117445
Nature. 2017 Feb 2;542(7639):115‐118; PMID 28117445
Take Home Points• Secondary Prevention: Patient Access, Seeing it, DiagnosticAccuracy
• Ideal Diagnostic Technology: Portable, Cheap,Accurate
• Validation is essential
1
Clinical and Pathologic Features of Indeterminate Cell Histiocytosis
Resident: Nathaniel Slater, MD
Attending: Natalie Sun, MD
UNC Department of Dermatology
NC Dermatology Summer Meeting
June 9, 2017
2
Our Case
• 55 yo man with a history of HTN and NAFLD presented with an asymptomatic, widespread papular eruption
• Complete ROS pan-negative
• Outside biopsy in June 2016 consistent with Langerhans Cell Histiocytosis (LCH)
• UCSF pathology consultation also favored LCH
3
Exam
2
Exam
4
Exam
5
6
Medical history
• Past medical hx» HTN, NAFLD, prior BCC
• Family hx» No autoimmune
disorders
» Mother: breast ca, 70s
» Brother: Hodgkin’s, 40s
» Pt is 1 of 10 children, no other FH of cancer
• Social hx» Environmental engineer,
married with 12yo child.
• Meds» Irbesartan 150mg daily
» Vascepa (rx fish oil) daily
» Omeprazole 40mg daily
» Sildenafil 100mg prn
• NKDA
3
7
Workup unrevealing for systemic diseasePET CTNo extra-cutaneous disease
Bone marrow biopsy
LabsAlk Phos 123 (H); CMP, CBC, ESR, LDH, IgG/A/M, Ferritin, Uric acid, U/A unremarkable
Normocellularmarrow with no evidence of LCH, langerinnegative.
No immuno-phenotypic
abnormalities on
flow cytometry
Single-system Cutaneous LCH?• Isolated skin disease is rare in adults
• Clinical manifestations: highly variable spectrum reported» Severe intertriginous or seborrheic dermatitis-like,
papulopustular, xanthomatous, purpuric, hemorrhagic, pigmented variants reported (Querings et al., Cardoso et al.)
• Course: highly variable, unpredictable» Numerous indolent cases reported
» Potential for persistence or progressive disease
• Gamut of treatments reported (mostly as case reports):
8
9
H&E c/w LCH
Top Right: low powerLeft, 20XBottom Right, 40X
4
Immunophenotype
10
CD1a
CD68
S100
Negative for:• Cytokeratin• Tryptase• Melan-A• Langerin (CD207)
Immunohistochemistry of Histiocytoses
11
Bolognia et al.
Dx: Indeterminate Cell Histiocytosis (ICH)
• Consistent with LCH» H&E c/w with LCH;
strong and diffuse CD1a positivity
» CD68+ and focal S100 not specific either way
• Favoring ICH» Langerin-
» Lack of epidermotropism, lack of eosinophils
» Clinical picture most consistent with reported cases of ICH
12
CD1a S100 CD68 Birbeckgranule
Langerin(CD207)
FactorXIIIa
LCH + + - / + + + -
ICH + + (or focal) + - - -
5
What Is ICH?• Enigmatic entity, displays LCH markers (CD1a; S100
which can be more focal), but also displays dermal histiocytic markers (CD68)
• Does not display Birbeck granules » Or Langerin (CD207)
• Somewhat controversial entity (< 50 cases reported, some have questioned whether this represents immature or de-differentiated LCH vs variant of non-LCH)» Multiple authors have suggested a spectrum between
Langerhans and non-Langerhans histiocytoses
» First described in 1985, incorporated into WHO classification in 2006
13
Clonality
• LCH » BRAFV600E in
approximately ½ of cases
• ICH » No BRAF mutation
» Clonal translocation in 3 of 4 ICH cases by next-gen sequencing and FISH
» Evidence for ICH as its own clonal entity
14
Clinical Features of ICH• Firm, red, yellow, or red-brown papules
• Isolated and (more commonly) generalized variants
• Predominantly affects adults; favors trunk and extremities
• Most without epidermal change (minimal epidermotropism)
• Clinical ddx: generalized eruptive histiocytoma, juvenile xanthogranuloma, congenital self-healing reticulohistiocytosis, PLC
• Behaves more like non-LCH / reactive macrocytic process» Most cases self-limited or non-progressive
» Largest series (18 pts): most with stable disease, 2 with slow cutaneous progression, 2 developed systemic dz
» Several reports associated with leukemia or low-grade B cell lymphoma 15
6
Additional Images of ICH
16
Logemann et al.
Zerbini et al.
Tardio et al.
Management of ICH• Case reports of response to: observation, UVB (3 cases
with good response), PUVA, low-dose MTX, isotretinoin, thalidomide, systemic anti-neoplastics
17
12 months of NB-UVB; Logemann et al.
Summary• Indeterminate cell histiocytosis is an indolent neoplastic vs
clonal reactive entity
• H&E similar to LCH; CD1a+, S100+ (focal), CD68+, Langerin (CD207) -
• Typically spares skin folds, without epidermal change
• Most cases self-limited or non-progressive, supporting conservative management» Our patient’s case cleared after UVB phototherapy
• Clinical follow-up indicated as there are a few reports of progressive disease or associated lymphoproliferative malignancy
18
7
References• 1. Sun W-G, Zhong L-S, Chen H. A Case of Adult Generalized Cutaneous Langerhans Cell Histiocytosis. Ann Dermatol.
2016;28(2):262-264. doi:10.5021/ad.2016.28.2.262.
• 2. Brown RA, Kwong BY, McCalmont TH, et al. ETV3-NCOA2 in indeterminate cell histiocytosis: clonal translocation supports sui generis. Blood. 2015;126(20):2344-2345. doi:10.1182/blood-2015-07-655530.
• 3. Calatayud M, Güell JL, Gris O, Puig J, Arrondo E, Huguet P. Ocular involvement in a case of systemic indeterminate cell histiocytosis: a case report. Cornea. 2001;20(7):769-771. http://www.ncbi.nlm.nih.gov/pubmed/11588435. Accessed October 22, 2016.
• 4. Campanati A, Simonetti O, Marconi B, et al. Purely cutaneous Langerhans’ cell histiocytosis in an adult woman. Acta Derm Venereol. 2009;89(3):299-301. doi:10.2340/00015555-0614.
• 5. Cardoso JC, Cravo M, Cardoso R, et al. Langerhans cell histiocytosis in an adult: good response of cutaneous lesions to acitretin. Clin Exp Dermatol. 2010;35(6):627-630. doi:10.1111/j.1365-2230.2010.03784.x.
• 6. Daoud MS, Dahl PR, Dicken CH, Phyliky RL. Indeterminate cell histiocytosis treated successfully with 2-chlorodeoxyadenosine.Cutis. 1997;59(1):27-31; quiz 32. http://www.ncbi.nlm.nih.gov/pubmed/9013068. Accessed October 22, 2016.
• 7. Ghanadan A, Kamyab K, Ramezani M, et al. Erratum: Indeterminate Cell Histiocytosis: Report of a Case. Acta Med Iran. 2015;53(9):593. http://www.ncbi.nlm.nih.gov/pubmed/26553091. Accessed October 22, 2016.
• 8. Ghanadan A, Kamyab K, Ramezani M, et al. Indeterminate cell histiocytosis: report of a case. Acta Med Iran. 2014;52(10):788-790. http://www.ncbi.nlm.nih.gov/pubmed/25369016. Accessed October 22, 2016.
• 9. Logemann N, Thomas B, Yetto T. Indeterminate cell histiocytosis successfully treated with narrowband UVB. Dermatol Online J. 2013;19(10):20031. http://www.ncbi.nlm.nih.gov/pubmed/24139371. Accessed October 22, 2016.
• 10. Oh CW, Ivan D, Curry JL, et al. A case of indeterminate dendritic cell tumor presenting with leonine facies. J Cutan Pathol. 2016;43(2):158-163. doi:10.1111/cup.12611.
• 11. O’Malley DP, Agrawal R, Grimm KE, et al. Evidence of BRAF V600E in indeterminate cell tumor and interdigitating dendritic cell sarcoma. Ann Diagn Pathol. 2015;19(3):113-116. doi:10.1016/j.anndiagpath.2015.02.008.
• 12. Park L, Schiltz C, Korman N. Langerhans cell histiocytosis. J Cutan Med Surg. 16(1):45-49. http://www.ncbi.nlm.nih.gov/pubmed/22417995. Accessed October 18, 2016.
• 13. Querings K, Starz H, Balda B-R. Clinical spectrum of cutaneous Langerhans’ cell histiocytosis mimicking various diseases. Acta Derm Venereol. 2006;86(1):39-43. doi:10.2340/00015555-0003.
• 14. Rosenberg AS, Morgan MB. Cutaneous indeterminate cell histiocytosis: a new spindle cell variant resembling dendritic cell sarcoma. J Cutan Pathol. 2001;28(10):531-537. http://www.ncbi.nlm.nih.gov/pubmed/11737523. Accessed October 22, 2016.
19
References• 15. Tardío JC, Aguado M, Borbujo J. Self-regressing S100-negative CD1a-positive cutaneous histiocytosis. Am J Dermatopathol.
2013;35(4):e57-9. doi:10.1097/DAD.0b013e31827adc72.
• 16. Varga E, Korom I, Polyánka H, et al. BRAFV600E mutation in cutaneous lesions of patients with adult Langerhans cell histiocytosis. J Eur Acad Dermatol Venereol. 2015;29(6):1205-1211. doi:10.1111/jdv.12792.
• 17. Vasef MA, Zaatari GS, Chan WC, Sun NC, Weiss LM, Brynes RK. Dendritic cell tumors associated with low-grade B-cell malignancies. Report of three cases. Am J Clin Pathol. 1995;104(6):696-701. http://www.ncbi.nlm.nih.gov/pubmed/8526215. Accessed October 22, 2016.
• 18. Wang C-H, Chen G-S. Indeterminate cell histiocytosis: a case report. Kaohsiung J Med Sci. 2004;20(1):24-30. doi:10.1016/S1607-551X(09)70080-4.
• 19. Wang P, Wang X, Hong J, Wang Z. Extensive cutaneous Langerhans cell histiocytosis in an elderly woman. J Dermatol. 2011;38(8):794-797. doi:10.1111/j.1346-8138.2010.01098.x.
• 20. Wood GS, Hu CH, Beckstead JH, Turner RR, Winkelmann RK. The indeterminate cell proliferative disorder: report of a case manifesting as an unusual cutaneous histiocytosis. J Dermatol Surg Oncol. 1985;11(11):1111-1119. http://www.ncbi.nlm.nih.gov/pubmed/3902927. Accessed October 22, 2016.
• 21. Yin R, Zheng W, Yang X, Hao F. Recurrent generalized indeterminate cell histiocytosis: a case report. J Am Acad Dermatol. 2010;63(1):e3-5. doi:10.1016/j.jaad.2009.10.010.
• 22. Zerbini MCN, Sotto MN, de Campos FPF, et al. Indeterminate cell histiocytosis successfully treated with phototherapy. Autops case reports. 6(2):33-38. doi:10.4322/acr.2016.038.
20
1
A Case of Gemcitabine-associated “Pseudocellulitis”Sean McGregor, DO, PharmD
Dermatology Resident, PGY-2
Wake Forest University School of Medicine
Department of Dermatology
Wake Forest Baptist Medical Center
History
• HPI: Patient is a 62 year-old female
− Stage IIB (T1N1M0) mixed neuroendocrine and adenocarcinoma of the pancreas
− Status post pylorus-sparing Whipple procedure
− Currently on single agent gemcitabine chemotherapy
− Developed fever, chills, and bilateral lower extremity swelling and redness 5 days after first dose of chemotherapy (1,000 mg/m2)
• Dermatology was consulted regarding bilateral lower extremity cellulitis
Wake Forest Baptist Medical Center
History
• Past Medical History− HTN, DM, HLD, and CVA
• Past Surgical History− Pylorus-sparing Whipple procedure
• Social History− Former smoker (45 pack-year history)
• Allergies− NKDA
2
Wake Forest Baptist Medical Center
History
• Current medications− Amlodipine 10 mg PO daily
− Gabapentin 300 mg PO TID
− Insulin detemir 10 units SQ daily
− Metoprolol tartrate 12.5 mg PO BID
− Pancrealipase 24,000 units PO TID
− Simvastatin 40 mg PO daily
− Pantoprazole 40 mg PO daily
− Piperacillin/Tazobactam 3.375 g IV Q8H
Wake Forest Baptist Medical Center
Physical Examination• Vital Signs: Temp: 99.7 (Tmax 101.3); BP: 145/72
mmHg; HR: 80 BPM; RR: 20/min; O2: 95% RA
Figure 1. Well demarcated erythema over distal lower extremities with 2+ lower extremity edema
Wake Forest Baptist Medical Center
Labs and Imaging
• WBC: 6.7 x 103/mm3
• HgB: 7.9 g/dL
• Hct: 24.6%
• PLT: 272,000/mm3
• Na: 134 mEq/L
• K: 4.2 mEq/L
• SCr: 0.48 mg/dL
• Glu: 232 mg/dL
• CT C/A/P− No evidence of pneumonia,
intra-abdominal abscess, or other infectious foci
• Venous Duplex US BLE− Negative for DVT
• Blood cultures− Negative x2
3
Wake Forest Baptist Medical Center
Assessment and Plan
• Differential Diagnosis− Stasis dermatitis
− Sclerosing panniculitis
− Non-purulent cellulitis
− Opportunistic (i.e. fungal/AFB) infection
− Cutaneous reaction to gemcitabine?
• Plan− Punch biopsy (4 mm) sent for H&E and tissue culture
Wake Forest Baptist Medical Center
Results
Figure 3. H&E, 200X; Mixed cellular infiltrate with neutrophils
Figure 4. H&E, 400X; Mixed cellular infiltrate with neutrophils
Figure 2. H&E, 10X; sparse inflammatory infiltrate
Wake Forest Baptist Medical Center
Discussion
• Gemcitabine is a pyrimidine antimetabolite− MOA: Inhibition of DNA synthesis
Inhibits DNA polymerase and ribonucleotide reductase
Cell cycle-specific for the S-phase and blocks cellular progression at G1/S phase
• Active against solid-organ malignancies
• Adverse reactions typically include nausea, vomiting, anemia, and neutropenia
• Cutaneous reactions are less common, but have been reported (up to 30%)
4
Wake Forest Baptist Medical Center
Discussion
• “Pseudocellulitis” is a broad term used to classify a subset of cutaneous reactions− Radiation recall dermatitis
− Erysipeloid eruptions
− Scleroderma-like eruptions
− Lipodermatosclerosis-like eruptions
• Pubmed search of “gemcitabine” and “pseudocellulitis” reveals 11 case reports
• Recent case series in JAAD proposed re-classification of the terminology− Acute Lipodermatosclerosis (ALDS)-like eruption
Wake Forest Baptist Medical Center
Discussion
• Mittal and Levanthal. JAAD Case Reports.2017;3:190-5.− A 76 year-old male with pancreatic cancer on adjuvant
gemcitabine
− New-onset erythema, edema and pain in bilateral lower extremities after 5th dose
− Afebrile and no leukocytosis
− Improved after topical clobetasol and compression therapy
Wake Forest Baptist Medical Center
Discussion
• Strouse and Epperla. J Oncol Pharm Practice. 2017;23(2):157-160.− A 62 year-old female with metastatic pancreatic cancer on
gemcitabine
− New-onset erythema, edema and pain in bilateral lower extremities after 2nd dose
− Had history of chronic edema in lower extremities
− Afebrile but leukocytosis present
− Biopsy showed neutrophilic infiltration
5
Wake Forest Baptist Medical Center
Discussion• Asemota, Reid, and Kovarik. JAAD Case
Reports.2015;1:178-81. − A 77 year-old male with stage IV NSCLC status post
radiation and carboplatin/pemetrexed chemotherapy on gemcitabine
− Acute onset bilateral lower extremity erythema after 3rd dose (similar reactions after prior doses)
− Afebrile and no leukocytosis
− Biopsy showed edema and sparse mixed inflammation with lymphocytes, neutrophils, and rare esosinophils
• Similar cases of radiation-recall dermatitis and “pseudocellulitis” over areas of ascities reported
Wake Forest Baptist Medical Center
Discussion• Mechanism of reaction is unclear
− Increased vascular permeability
− Direct endothelial damage
− Release of vasoactive cytokines
• Widely distributed in tissues− Vd ranges from 50-370 L/m2 (depending on infusion time)
− Lipophilic and readily diffuses into extracellular compartment
• Decreased clearance and accumulation in cutaneous and subcutaneous tissues with resultant local toxicity?
Wake Forest Baptist Medical Center
Discussion
• Typically occurs on the lower extremities
• Patients often have bilateral involvement
• Develops within 2-5 days of gemcitabine infusion
• Leukocytosis and fever are usually absent− However, both have been reported
• May be associated with peripheral edema− Patients with underlying venous stasis may have higher
risk of ALDS-like reaction
6
Wake Forest Baptist Medical Center
Discussion
• Problem — clinical confusion regarding diagnosis
− Overlapping clinical features with cellulitis
− Gemcitabine independently associated with fever (40%) and peripheral edema (15-20%)
− Patients are often treated with antibiotics for presumed cellulitis
Wake Forest Baptist Medical Center
Discussion
• Treatment− Topical corticosteroids
− Compression therapy
− Leg elevation
− NSAIDs
− Discontinuation of gemcitabine?
Most patients continue treatment despite reaction
Reaction usually self-limited
Patients typically improve after 1-2 weeks
Recurrence usually occurs in similar distribution
Wake Forest Baptist Medical Center
Discussion
• Condition is underrecognized and underreported
• Recognition is important− Avoids interruption in treatment
− Avoids unnecessary use of antibiotics
− Avoids unnecessary hospitalization
− Avoids unnecessary costs and complications
• Our recommendations:− Triamcinolone 0.1% ointment BID
− Leg elevation
− Compression therapy
7
Wake Forest Baptist Medical Center
References• 1: Mittal A, Leventhal JS. Gemcitabine-associated acute lipodermatosclerosis-like eruption: An underrecognized phenomenon. JAAD Case Rep.
2017 Apr 14;3(3):190-195.doi: 10.1016/j.jdcr.2017.02.014. eCollection 2017 May. PubMed PMID: 28443306;PubMed Central PMCID: PMC5394206.
• 2: Strouse C, Epperla N. A rash diagnosis: Gemcitabine-associated pseudocellulitis. J Oncol Pharm Pract. 2017 Mar;23(2):157-160.doi10.1177/1078155216635852. Epub 2016 Jun 23. PubMed PMID: 26946530.
• 3: Curtis S, Hong S, Gucalp R, Calvo M. Gemcitabine-Induced Pseudocellulitis in a Patient With Recurrent Lymphedema: A Case Report and Review of the Current Literature. Am J Ther. 2016 Jan-Feb;23(1):e321-3. doi:10.1097/MJT.0000000000000024. Review. PubMed PMID: 24451298.
• 4: Ruiz-Casado A, Gutiérrez D, Juez I. Erysipeloid rash: A rare adverse event induced by gemcitabine. J Cancer Res Ther. 2015 Oct-Dec;11(4):1024. doi:10.4103/0973-1482.148711. PubMed PMID: 26881588.
• 5: Dasanu CA, Bockorny B. Recurrent pseudocellulitis due to gemcitabine: underrecognized and underreported? J Oncol Pharm Pract. 2015 Oct;21(5):377-9. doi: 10.1177/1078155214531610. Epub 2014 Apr 24. PubMed PMID: 24769519.
• 6: Asemota E, Reid E, Kovarik C. Gemcitabine-induced pseudocellulitis in a patient with non-small cell lung carcinoma. JAAD Case Rep. 2015 Jun 8;1(4):178-81. doi: 10.1016/j.jdcr.2015.04.007. eCollection 2015 Jul. PubMed PMID: 27051723; PubMed Central PMCID: PMC4808723.
• 7: Obeid KM, Venugopal AA. Gemcitabine-associated "pseudocellulitis" and "pseudosepsis": a case report and review of the literature. Am J Ther. 2013 Jan;20(1):118-20. doi: 10.1097/MJT.0b013e3182204ffe. Review. PubMed PMID 21768869.
• 8: Singh A, Hampole H. Gemcitabine associated pseudocellulitis. J Gen Intern Med. 2012 Dec;27(12):1721. doi: 10.1007/s11606-012-2101-x. Epub 2012 Jun 14. Erratum in: J Gen Intern Med. 2013 Apr;28(4):600. PubMed PMID: 22696254; PubMed Central PMCID: PMC3509303.
• 9: Korniyenko A, Lozada J, Ranade A, Sandhu G. Recurrent lower extremity pseudocellulitis. Am J Ther. 2012 Jul;19(4):e141-2. doi: 10.1097/MAJ.0b013e318245fdaa. PubMed PMID: 22772033.
• 10: Tan DH, Bunce PE, Liles WC, Gold WL. Gemcitabine-related "pseudocellulitis": report of 2 cases and review of the literature. Clin Infect Dis. 2007 Sep 1;45(5):e72-6. Epub 2007 Jul 20. Review. PubMed PMID: 17682983.
• 11: Zustovich F, Pavei P, Cartei G. Erysipeloid skin toxicity induced by gemcitabine. J Eur Acad Dermatol Venereol. 2006 Jul;20(6):757-8. PubMed PMID:16836522.
• 12: Kuku I, Kaya E, Sevinc A, Aydogdu I. Gemcitabine-induced erysipeloid skin lesions in a patient with malignant mesothelioma. J Eur Acad Dermatol Venereol. 2002 May;16(3):271-2. PubMed PMID: 12195570.
Wake Forest Baptist Medical Center
Thank you!Questions?
1
A rare cause of breast ulceration:diffuse dermal angiomatosis
July 9, 2017
Diana Norton, MDAngelica Selim, MD, & Claude Burton, MD
Clinical Presentation
70 yo lady with four months of painful non-healing ulcerations on the breast
Past medical history
- Severe obesity, BMI 47 with macromastia
- Venous insufficiency—leg ulcers x1 year and varicose veins s/p radio frequency ablation
- Former smoker
- No breast cancer
2
Differential diagnoses
MALIGNANCY Trauma
- Bras, seatbelts
- Radiation
Vascular
- Pyoderma gangrenosum
- Diffuse dermal angiomatosis
Infection
- Cellulitis, mastitis
- Zoster
Diffuse dermal angiomatosis
• Benign vascular disorder
• Cutaneous reactive angiomatosis
• Causes:– Local ischemia hypoxic stimulus
increased vascular endothelial growth factor
– Vascular occlusion emboli neoangiogenesis
Locations
• Lower extremities in severe atherosclerotic disease (majority of cases)
• Forearm adjacent to fistula in dialysis patient
• Pendulous breasts of women
3
Reports in the literature
Biopsy results
• Diffuse proliferation of endothelial cells lining capillary sized vessels in the reticular dermis
• Our patient:
– Acanthosis, dermal edema, chronic inflammation
4
Largest case series
Risk factors
5
Treatment options
Isotretinoin 50mg daily
Taper over several months
Our patient
Diligent wound care with ulcer resolution in 2 months without recurrence on 5 month follow up
Summary
• Diffuse dermal angiomatosis is a rare and poorly studied disease
• Consider in women with pendulous breasts and smoking history
• Biopsy may be helpful if it reveals proliferating vessels in the dermis
• No consensus on therapy—wound care, isotretinoin, surgery, revascularization
References1. Adams BJ, Goldberg S, Massey HD, Takabe K. A cause of unbearably painful breast, diffuse dermal angiomatosis. Gland Surg. 2012 Aug 1;1(2)PubMed PMID: 24353983; NIHMSID: NIHMS470113; PubMed Central PMCID: PMC3864042.2. Kimyai-Asadi A, Nousari HC, Ketabchi N, Henneberry JM, Costarangos C. Diffuse dermal angiomatosis: a variant of reactive angioendotheliomatosis associated with atherosclerosis. J Am Acad Dermatol. 1999 Feb;40(2 Pt 1):257-9. PubMed PMID: 10025757.3. Requena L, Fariña MC, Renedo G, Alvarez A, Yus ES, et al. Intravascular and diffuse dermal reactive angioendotheliomatosis secondary to iatrogenic arteriovenous fistulas. J Cutan Pathol. 1999 Mar;26(3):159-64. PubMed PMID: 10235383.4. Reusche R, Winocour S, Degnim A, Lemaine V. Diffuse dermal angiomatosis of the breast: a series of 22 cases from a single institution. Gland Surg. 2015 Dec;4(6):554-60. PubMed PMID: 26645009; PubMed Central PMCID: PMC4647012.5. Rongioletti F, Rebora A. Cutaneous reactive angiomatoses: patterns and classification of reactive vascular proliferation. J Am Acad Dermatol. 2003 Nov;49(5):887-96. PubMed PMID: 14576670.6. Sriphojanart T, Vachiramon V. Diffuse Dermal Angiomatosis: A Clue to the Diagnosis of Atherosclerotic Vascular Disease. Case Rep Dermatol. 2015 May-Aug;7(2):100-6. PubMed PMID: 26120304; PubMed Central PMCID: PMC4478308.7. Tollefson MM, McEvoy MT, Torgerson RR, Bridges AG. Diffuse dermal angiomatosis of the breast: clinicopathologic study of 5 patients. J Am Acad Dermatol. 2014 Dec;71(6):1212-7. PubMed PMID: 25264238.8. Villa MT, White LE, Petronic-Rosic V, Song DH. The treatment of diffuse dermal angiomatosis of the breast with reduction mammaplasty. Arch Dermatol. 2008 May;144(5):693-4. PubMed PMID: 18490610.
1
The Clinical Relevance of “Atypia” in a Dermatopathology Report
Paul B Googe, MD
Professor and Laboratory Director
UNC Dermatopathology Laboratory
Department of Dermatology
Atypia
• Abnormalities in pattern of growth, anatomic location
• Cytological abnormalities
– Cell size
– Nuclear configuration
– Nuclear to cytoplasmic ratio
– Cytoplasmic changes
– Nucleoli
2
Atypia
• Mitotic activity
• Necrosis
• Size of tumor
• Staining characteristics
– Unusual or aberrant immunohistochemical staining results
• Cytokeratin positivity in melanoma or sarcoma
• Cytokeratin 20 negative Merkel cell carcinoma
April June
July
3
Atypia
• Difficulty in classification or ability to recognize a neoplasm
– lack of familiarity
– uncertainty
• Pathologic findings inconsistent with clinical, imaging, past medical history or laboratory findings
Definitions:
• Benign – may persist and enlarge, may clinically reappear if incompletely removed, but not expected to be locally destructive or metastasize or be fatal
• Atypia – same as benign
– In some tumor constructs may relate to propensity for local recurrence or persistence and/or limited metastatic phenomenon
• Malignant – May be locally destructive, metastasize or be fatal
4
Important observations:
– Benign tumors can recur
– Well described phenomenon of some types of benign tumors that show regional lymph node presence
• Cellular blue nevi
• Congenital nevi
• Hidradenoma
– Malignant tumors do not necessarily metastasize and are not uniformly fatal
– Heterogeneity of neoplasia with regard to lethal potential
– Genotype of a neoplasm may or may not be predictive of lethal potential
– Pathologic findings may provide information that is of prognostic use based on statistics, but prognosis of an individual may simply not be accurately predicted in some forms of neoplasia
Recurrent/Persistent Clear Cell Hidradenoma
2005 2011 2012
“Atypia” in benign neoplasms
• Dermatofibroma
• Seborrheic keratosis
• Melanocytic nevi
• Hidradenoma
• Pilar tumor
5
“Atypical” neoplasms that have benign behavior
• Dysplastic nevi
• Atypical spitz nevus
• Atypical proliferating pilar tumor
• Atypical pilomatricoma
• Atypical hidradenomas
• Atypical cellular blue nevus
• Atypical intradermal smooth muscle neoplasm
What are dysplastic nevi?
• Dysplastic nevi are benign melanocytic neoplasms which have clinical and histological attributes that resemble what may be seen in early or evolving melanoma.
• Dysplastic nevi occur sporadically and in kindreds with familial melanoma.
• Dysplastic nevi have a histological pattern with certain, consistent features
Dysplastic Nevus
Major Criteria
1. Basilar proliferation of melanocytes, often with nesting, usually extending beyond a dermal nevic component, if present
2. Melanocytic atypism
6
Melanocytic atypism in dysplastic nevi
• Increase in cell size
• Increase in size of nucleus
• Nuclear hyperchromasia
• Shape of nucleus
• Cytoplasmic alterations – pigment granules
Minor Criteria
1. Inflammatory infiltrate
2. Increased vascularity with evidence of endothelial‐cell hypertrophy
3. Concentric eosinophilic fibrosis and/or lamellar fibroplasia
4. Bridging of rete by nests of melanocytes
Inflammatory Infiltrate
7
Increased vascularity
Concentric eosinophilic fibrosis
Lamellar fibroplasia
8
Bridging of rete by nests of melanocytes
DYSPLASTIC NEVUS, DIAGNOSTIC TERMINOLOGY, HISTOPATHOLOGIC
after Clark et al, WHO
• nevus with features of a dysplastic nevus
• dysplastic nevus with mild atypia
• dysplastic nevus with moderate atypia
• dysplastic nevus with severe atypia
N.I.H. Consensus Statement
• nevus with architectural disorder
• nevus with architectural disorder and mild melanocytic atypia
• nevus with architectural disorder and moderate melanocytic atypia
• nevus with architectural disorder and severe melanocytic atypia
Ackerman“Clark’s nevus”
Clinical attributes of dysplastic nevi
• Larger than 5 mm
• Variability in contour
• Variability in color
9
Treatment of Dysplastic Nevus
Features of, Mild atypia or Moderate atypia
‐ No re‐excision unless
– Partial sampling
– Concern for malignancy remains
Severe Atypia
– Complete removal
Atypical Spitz Nevus
Atypical cellular blue nevus
10
Smooth muscle actin
Atypical intradermal Smooth Muscle Neoplasm
“Atypical” neoplasms that have malignant potential or are early patterns of malignancy
• Atypical fibroxanthoma
• Atypical lentiginous melanocytic hyperplasia
• Atypical vascular proliferation after radiation therapy
11
Atypical Fibroxanthoma
• Dermal based neoplasm• Sun damaged skin older people• Head and neck• Microscopically highly malignant, sarcoma‐like• Infrequently recur locally• Rarely metastasize• Small diameter ( typically 1 cm or so)• Nonpigmented, sometimes ulcerated• No horn• Differential diagnosis: poorly differentiated SCC, desmoplastic melanoma
12
CK AE1/AE3
Vimentin
13
Clear cell Atypical fibroxanthoma
VimentinCD10
Case: Clinical History
• 73 year old white male presents to dermatology clinic for two new lesions developing on vertex of head (4/6/2011)
• 2 lesions measuring 1.5 cm each– red, nodular, with smooth borders
• Hx significant for multiple SCCs• Hx of Radiation Treatment to the Right side of head x 30
– Unknown amounts of occupational radiation exposure
• Biopsy of both lesions performed and submitted for pathology
14
Consistent with Aypical Fibroxanthoma (AFX)
• Spindle cell lesion in the dermis
• No perivascular or perineural invasion
• No necrosis
• No invasion into subcutis
• High mitotic activity with pleomorphic nuclei
Clinical History
• Patient returns to dermatology clinic 20 months later (11/17/2011)
– 4 recurrent nodules on vertex of head
• Clinical exam is similar to the previous presentation
• Pathology diagnosis is AFX
– Similar histology to previous biopsy
• Patient is referred for wide local excision
15
Satellite Metastasis
16
Immunohistochemistry
• Negative staining
– AE1/3, S100, Melan‐A, Tyrosinase, SMA, Desmin, CD34, CD31, CK5/6, 34be12, p63, Sox 10
• Positive staining
– Vimentin, Procollagen, CD10
AFX with subcutaneous involvement, present in deep margin = pleomorphic dermal sarcoma
17
Pleomorphic Dermal Sarcoma
• Term proposed by C.D. Fletcher
• Miller K, Goodlad JR, Brenn T. Pleomorphic dermal sarcoma: adverse histologic features predict aggressive behavior and allow distinction from atypical fibroxanthoma. Am J Surg Pathol. 2012 Sep;36(9):1317‐26
Pleomorphic Dermal Sarcoma
• Differentiated histologically from AFX by– Necrosis
– Ulceration
– Deep subcutaneous invasion
– Lymphovascular invasion
– Perineural invasion
• Significant overlap of clinical picture, histology, and prognosis with AFX• May be considered a part of a spectrum
Atypical Fibroxanthoma (small)vs
Pleomorphic dermal sarcoma (big)
• Atypical fibroxanthoma
• Dermal
• Typically less than 2 cm
• Undifferentiated stromal neoplasm
• Tert mutation
• Sometimes recur
• Rarely metastasize
• Pleomorphic dermal sarcoma
• Subcutaneous
• 2 cm or greater
• Vascular/perineural invasion
• Undifferentiated stromal neoplasm
• Tert mutation
• Sometimes metastasize
18
Recurrent AFX
19
No Residual TumorMargins Free
Patient/Tumor Features Associated With Bad Outcome With Skin Cancers
• Advancing age
• Immunosuppression (organ transplant)
• Chronic lymphocytic leukemia
• Large tumor diameter, deep/thick invasion, perineural invasion
• Head and neck location
• Local recurrence
20
Questions to consider in “atypical” cases
• Is the neoplasm properly classified ?• Is the atypia a recognized phenomenon to occur in the class of neoplasm specified?
• Was the lesion well sampled and evaluable?• How many special stains or studies were used to arrive at the conclusion?
• Is there a pertinent reference in the literature that substantiates the classification used?
• What are the consequences to patient management?• Is there potential for bad or unexpected outcome?
Grading and Staging of Neoplasia
• Histologic grade – How malignant does it look under microscope?
• High grade – bad – high risk for metastasis and death• Low grade – good – may recur locally, show limited metastatic potential and are unlikely to cause death
• Intermediate grade ‐ ? – depends on type of tumor
• Staging– How big? Volume of tumor– Anatomic compartment– Regional metastasis– Distant metastasis
Trust, but Verify
Management of “Atypical” Neoplasms
21
Management of “Atypical” Neoplasms
• Complete removal with a margin of normal tissue
• Thorough pathologic analysis
• Follow up» Clinical evaluation of regional lymph nodes
» Consider imaging
» Specialty clinic or specialist to assist in follow up care
• Repeat tissue sampling of potential recurrences or metastases
• Reassure patient and educate » Enlist patient/family to help watch for reappearance or new
lesions
» Don’t make promises6/23/2017 61