Dermatology for the InternistA Focus on Skin Cancer

February 2020

Ashley Crew, MDAssociate Professor, Department of Dermatology

Disclosures

• None

Why am I Here?

• Quick eConsult reminders

– thanks for the great consults!

– Photo reminders

– Hopefully helping you to learn

• Review some cases – focus on skin cancer this time

Follow up from last year

eConsult (and TD in general)

• Please include

– good/pertinent history

– solid photos

History Refresher (shameless plug:))

• One of the challenges of S&F teledermatology is an adequate history given the lack of FTF care (***inverse relationship between likelihood of FTF and number of characters in a consult)

• Include a pertinent history:

– Lesions- location, duration, changes, associated symptoms, family history

– Rashes- distribution, duration, symptoms (systemic), prior treatments, exposures

– PMH

– Medications (most pertinent with rashes)

– Allergies

Photo Refresher“If you can’t see it, we can’t see it!”

• Background: solid, neutral color with non-reflective surface

• Lighting: diffuse indirect lighting, avoid shadows

Lesions

• Location: distance for perspective and close-up views with anatomical landmark (in focus in focus in focus)

• Size: may include a millimeter ruler near the lesion

Rashes

• Location:

– Far view with anatomical landmark and to appreciate distribution

– All involved areas• Krupinski E et al. American Telemedicine Association’s practice guidelines for teledermatology. Telemedicine

and e-Health 2008;14:289-302.

• McKoy K et al. Quick Guide to Store-Forward Teledermatology for Referring Providers. 2012.

Nevi

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COMMON ACQUIRED

MELANOCYTIC NEVI Hamartomas vs. benign proliferation of nevus cells

with growth advantage

Increase in number and peak in 3rd decade

Caucasians > Asian/African Americans

Acral, conjuctival nevi more common in Asian/African Americans

Genetic factors, especially in familial melanoma, and sun exposure

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COMMON ACQUIRED

MELANOCYTIC NEVIClassification

Junctional - Proliferation of slightly altered melanocytes within the epidermis

Compound - Migration to the dermis

Intradermal - Loss of nevus cells in the epidermis

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JUNCTIONAL NEVUS

12

COMPOUND NEVUS

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INTRADERMAL NEVUS

EVALUATING PIGMENTED LESIONS1. For adult patients, has it remained about the same for

the last year or so?

2. Is it basically symmetric, with even borders and primarily one color?

3. Is it relatively similar to other moles on the patient

SUMMARY: If it’s small (< 1.5 cm), been there for many years and is not changing, it’s not likely to be a melanoma.

DYSPLASTIC NEVI

Also called atypical or Clark’s nevus

Found in 2-18% of population

Marker for increased risk of melanoma-10% or more chance

DYSPLASTIC NEVI

Usually larger than other nevi and have variation in pigment

3 of 5 of these criteria:

Poorly defined borders

Irregular border

Irregular pigment

Background erythema

Larger than 5 mm

DYSPLASTIC NEVUS SYNDROME

Patients with large numbers of dysplastic nevi (>50)

Have a family history of dysplastic nevi and/or melanoma

Risk of melanoma increased

‘UGLY DUCKLING’ SIGN

Melanocytic nevi in the same patient tend to resemble one another

Melanoma often has a different pattern than the other nevi

This has been called the “ugly duckling” sign

‘UGLY DUCKLING’ SIGN

Nevi must be evaluated in the context of the individual patient

All of a patient’s nevi may be atypical in some way, because that is the type of nevi they make

If there is one nevus that stands out to you, it is the “ugly duckling”

Courtesy Heather Wickless, M.D.

If you could only biopsy 1 lesion, which would it be?

A,B,D, and E are all similar and show a net-like (reticular) pattern, with hypopigmentation around hair follicles

C is asymmetric, with two islands of pigmentation, with a reticular pattern and small globules. It sticks out as the “ugly duckling”

Based on the clinical features, biopsy of the lesion was diagnosed as an atypical nevus by a dermatopathologist

Management of dysplastic nevi is controversial, but the patient and physician decided to conservatively re-excise the lesion

The patient was counseled about his increased risk of melanoma (in light of large number of common acquired nevi >100)

Skin Cancers

A few anyway

Skin cancer overview

• Epidermal Carcinomas:– Basal cell carcinoma– Squamous cell carcinoma– Merkel cell carcinoma

• Melanoma:• Adnexal Tumors: Sebaceous carcinomas, Microcystic Adnexal

Carcinomas• Sarcomas: Dermatofibrosarcoma Protuberans Atypical

Fibroxanthoma, Undifferentiated Pleomorphic Sarcoma, Pleomorphic Dermal Sarcomas, Leiomyosarcoma

Non-Melanoma Skin Cancer:

99% of skin cancers

38 year old male, noted during haircut

Melanoma

MELANOMA EPIDEMIOLOGY

91,270 new cases of melanoma and 9,320 expected deaths from melanoma in the US in 2019

Lifetime risk has increased from

1 in 1500 persons born in the early 1900’s

1 in 50 of Caucasians born in 2014

1 in 200 for Hispanics, 1 in 1000 for African Americans

Melanoma can affect all ages

https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html

IS IT AN EPIDEMIC?

Increasing incidence but stable mortality and late stage disease

Explanations?

Early diagnosis and improved therapy?

Over diagnosis with increased numbers of biopsy and increased scrutiny?

Welch HG Br Med J 2005

MELANOMA RISK FACTORS UV radiation

Presence of dysplastic nevi

Family History of Melanoma

Personal History of Melanoma

Congenital melanocytic nevi

Fitzpatrick Skin Type

Immune suppression

Age

Male gender (1:57) vs female gender (1:81)

HERIDITARY RISKS IN MELANOMA

Majority of melanomas are sporadic, but a small percentage have a genetic basis (CDKN2A, CDK4, BRCA2, p53, etc).

+ Family History results in 50% chance of developing melanoma by age 50

Have an increased risk to develop a second primary melanoma

Consider referral to medical genetics if greater than 3 family members have melanoma

50% of familial melanoma have no identified genetic mutation

SUPERFICIAL SPREADING

MELANOMA

LENTIGO MALIGNA MELANOMA

NODULAR MELANOMA

ACRAL LENTIGINOUS MELANOMA!

ACRAL LENTIGINOUS MELANOMA!

Q- What is the next step if you suspect a melanoma?

39

Cryosurgery (liquid nitrogen)

Excisional biopsy

Clinical monitoring with photography

Electrodessication and curettage

Diagnosis requires histological confirmation

In cases of high clinical suspicion, excisional biopsy is ideal!

Increased rates of misdiagnosis with incisional (partial) biopsies or shave biopsies

Diagnosis: Biopsy TechniquesBiopsy for initial diagnosis is critical for determining

appropriate treatment

• Punch Biopsy

• Shave Biopsy

• Excisional Biopsy

TREATMENT

Surgical resection

Chemotherapy

Radiation Therapy

Immunotherapy

TRADITIONAL ADJUVANT THERAPY

Chemotherapy

IFN alpha 2b

Interleukin-2

NEW THERAPEUTICS Immunotherapy

Ipilimumab

Antibody directed against CTLA-4 (cytotoxic T-lymphocyte associated antigen)

Activates cytotoxic lymphocytes against tumor

Nivolumab

Antibody that inhibits PD-1 on cells

Activates cytotoxic

lymphocytes against

tumor

Onycolytic virus

Talimogene laherparepvec (TVEC)

Engineered herpes virus that kills tumor cells and augments immunity (via GMCSF)

Targeted molecular

Vemurafenid/Dabrafenib/Trametinib

Targets common BRAF mutation in melanoma

MEK inhibition

PREVENTIONA large study in Australia showed that regular

use of sunscreen decreases the risk of melanoma

THE BASICS OF PREVENTION

Sun Avoidance!

Sun Avoidance!

Sun Avoidance!

Sun Avoidance!

Sun Avoidance!

• Sun Avoidance:

– Avoid sun during peak hours of 10 am – 3 pm– Seek shade

• Sun Protection:

– Broad spectrum sunscreen– SPF 30 or higher – 50+ is more effective– Sun protective clothing - UPF

THE BASICS OF PREVENTION

THE BASICS OF PREVENTION

Non-melanoma Skin Cancer (NMSC)

53 year old female, “pimple” that isn’t healing

NMSC Overview• Non-Melanoma Skin Cancer has become an epidemic:

NMSC Overview• NMSC has become an epidemic:

• Incidence – 1,200,000 (1994) 5,434,193 (2012)

• Annual incidence 3-4 times greater than all other types of cancer combined

JAMA Dermatol. 2015 Oct;151(10):1081-6. doi: 10.1001/jamadermatol.2015.1187.

American Cancer Society. Cancer Facts & Figures 2013. Atlanta, GA: American Cancer Society; 2013.

Economic burden• Costs are increasing:

– Annually 5 million individuals treated

– Annual cost $8.1 billion6

Prevalence and costs of skin cancer treatment in the U.S., 2002-2006 and 2007-2011. American Journal of Preventive Medicine

Basal cell carcinoma• Most common type of skin cancer

– BCC:SCC 4:1

– Male: Female 1.5:1

• Median Age of Diagnosis: 68 years

• Locally destructive, low risk of regional or distant metastasis

• Association with other cancers:

– 20% of patients with frequent BCC (>6) had mutations in DNA repair genes

– RR any cancer 3.5 (>6 BCC)

– RR increased for Melanoma (11.9), Colon (4.2), Ovarian (51.4)

• Subtypes:

– Superficial

– Nodular

– Aggressive

JCI Insight. 2018 Aug 9;3(15). pii: 122744. doi: 10.1172/jci.insight.122744.

SQUAMOUS CELL CARCINOMA

Actinic Keratosis• Dysplastic keratinocytes that are UV induced and act as

precursor lesions to SCCis and SCC• Temples and cheeks are most common location• Risk of malignant transformation: range from 0.025-20%

• Risk of progression in Veterans Affair Population:– SCC (invasive or in-situ):

• 1 year: 0.6%• 4 years: 2.57%

– BCC:• 1 year: .48%• 4 years: 1.56%

Cancer. 2009 Jun 1;115(11):2523-30. doi: 10.1002/cncr.24284.

SCC overview

Subtypes:

– SCCis

– Well differentiated – KA Type

– Moderately Differentiated

– High Risk/Aggressive

• Poorly Differentiated

• Acantholytic

Cancer. 2009 Jun 1;115(11):2523-30. doi: 10.1002/cncr.24284.

Not all SCC’s are created equal

• More overall deaths associated with SCC than Melanoma

– Melanoma deaths: 9,320

– SCC: 15,000

• Risk of metastasis depends on risk factors:

– Patient characteristics

– Tumor characteristics

https://www.skincancer.org/skin-cancer-information/skin-cancer-facts#melanoma

Patient characteristics: High risk

• HIV: Immune dysfunction, impaired T-Cell immune surveillance– 2x Risk

• Immune Modulating Medications:– Use is on the rise

• Solid Organ Transplant Patients:– Over 34,000 transplants performed per year

• Kidney > Liver > Heart > Lung > Pancreas > Intestine

J Natl Cancer Inst. 2013 Mar 6;105(5):350-60. doi: 10.1093/jnci/djs529. Epub 2013 Jan 4.

SOTR: Special considerations

• Skin cancers represent 95% of cancers in organ transplant recipients

• Risk of BCC is 10x greater

• Risk of SCC is 65-100x greater

• Melanoma risk is 3x greater, Kaposi Sarcoma is 84x greater

• Skin cancers are associated with higher morbidity and mortality

J Am Acad Dermatol. 2011 Aug;65(2):253-261. doi: 10.1016/j.jaad.2010.11.062.

• Risk Factors• Tumor > 2 cm

• Poorly differentiated

• Perineural Invasion

• Tumor invasion beyond

subcutaneous fat

• 92% of deaths from cSCC occurred in the AJCC 7th Edition T2 Category

• T2b accounted for only 19% of tumors – but the cohort accounted for 72% of nodal metastasis and

83% of deaths from cSCC

• 5 year risk of nodal metastasis is 37%

Tumor characteristics: High risk

SCC Summary

• Staging of SCC is critical to appropriate management – not all are created equal!

• Risk factors for SCC local recurrence and metastasis include: size, differentiation, PNI, depth of involvement, lymphovascular invasion and tumor location

• High risk SCC (AJCC T3/BWH T2b) are best managed in a multidisciplinary setting

Management SKIN CANCER

• Electrodessication and curettage– Small and superficial lesions on trunk– Higher recurrence rates with no margin assessment

• Wide Local Excision (Standard Excision)

• Mohs Micrographic Surgery

• Radiation Therapy

Early Diagnosis and Effective Surgical Therapy Represents the Best Treatment for Skin Cancer

Standard excision vs. mohs

100% of margin

examined

<1% of margin

examined

A fun rash

40 yo M w rash

40 yo M w rash

Tinea Versicolor

• Thin hypo or hyperpigmented plaques

• Usually asymptomatic

• Fine scale with stretching of the skin

• Often precipitated with hot/humid conditions

• Benign superficial fungal infection (malesssazia-> conversion to filamentous form)

• Sometimes recalcitrant

• Ddx- syphilis, psoriasis, vitiligo

Tinea Versicolor

• Treatment

– Ketoconazole shampoo as body wash daily for 2 weeks

– If needed repeat weekly as ppx “fungal Fridays”

• Reminder-

– Pigment often takes several additional weeks to return to normal

– Sun exposure accentuates pigment differences

Thank you!

72

Ashley B. Crew, MDAssociate Professor, Department of Dermatology

Director, Residency Training ProgramCo-Director Rheumatology-Dermatology Clinic

Keck School of MedicineUniversity of Southern California

. Crew, MDAssistant Professor, Department of Dermatology Associate Director, Residency Training Program

Keck School of MedicineUniversity of Southern California

Photo Refresher“If you can’t see it, we can’t see it!”

• Background: solid, neutral color with non-reflective surface

• Lighting: diffuse indirect lighting, avoid shadows

Lesions

• Location: distance for perspective and close-up views with anatomical landmark (in focus in focus in focus)

• Size: may include a millimeter ruler near the lesion

Rashes

• Location:

– Far view with anatomical landmark and to appreciate distribution

– All involved areas• Krupinski E et al. American Telemedicine Association’s practice guidelines for teledermatology. Telemedicine

and e-Health 2008;14:289-302.

• McKoy K et al. Quick Guide to Store-Forward Teledermatology for Referring Providers. 2012.

Photo Refresher“If you can’t see it, we can’t see it!”

• Background: solid, neutral color with non-reflective surface

• Lighting: diffuse indirect lighting, avoid shadows

Lesions

• Location: distance for perspective and close-up views with anatomical landmark (in focus in focus in focus)

• Size: may include a millimeter ruler near the lesion

Rashes

• Location:

– Far view with anatomical landmark and to appreciate distribution

– All involved areas• Krupinski E et al. American Telemedicine Association’s practice guidelines for teledermatology. Telemedicine

and e-Health 2008;14:289-302.

• McKoy K et al. Quick Guide to Store-Forward Teledermatology for Referring Providers. 2012.

Cases- “rashes”

40 yo male, chronically itchy left lower extremity, has tried HCT cream to no avail

Lichen Simplex Chronicus

• Epidermal hypertrophy that results from chronic rubbing/scratching of the skin

• Most frequently seen in older adults

• Itches spontaneously

• Predilection for the posterior neck, occipital scalp, anogenital region, shins, ankles, dorsal hands, feet and forearms

Lichen Simplex Chronicus-Treatment

• Often recalcitrant

• Identify a trigger if possible- dry skin, atopy, anxiety, OCD, underlying cause of pruritus

• Behavioral changes

• Topical steroids! (more on that in a moment)

• Occasionally intralesional steroids

A word on topical steroids

• The big three– Hydrocortisone 2.5%- safe for (limited) use on the face,

groin and in the axillae

– Triamcinolone 0.1%- “work horse” of steroids, good for when a larger body surface area is being treated

– Lidex 0.05%- high potency, more recalcitrant lesions

A word on topical steroids

• Also consider – Vehicle- ointment, cream, solution- for ease of use

– Volume- adequate to treat involved areas (FTU)

– Duration- guidelines for use M-F, 3 weeks on/1 week off

– Remind patients about inappropriate places to use the steroid

In the family

• Prurigo Nodularis

• Discrete, not plaque like

• Also difficult to treat but same principles apply

60 yo female with itchy bilateral lower extremity rash

Nummular Dermatitis/Eczema

• Men over 50, on the lower extremities

• Women slightly younger, seen on arms and legs

• Very itchy!

• Often impetiginized

Nummular Eczema

• Patients often have a history of atopy (allergic rhinitis, asthma, atopic dermatitis)

• Treatment

– Moderate to high potency topical corticosteroids (usually triamcinolone as a base, can increase to lidex)

– Good dry skin care

– Occasionally antimicrobials (oral or topical)

Dry Skin Care

• Mild soap

– Dove bar

– Wash with your hands only

• No scrubbing in the shower

• Moisturize within 3 minutes of getting out of the shower

– The thicker the better (scoop don’t pump)-Eucerin, Aquaphor, CeraVe cream

Nummular Eczema

• If not improving or atypical appearing, consider the differential diagnosis – Mycosis fungoides (not usually as itchy, often with lesions

on the buttocks and trunk)

– Lichen simplex chronicus (requires higher potency steroids for longer)

– Contact dermatitis (well defined borders)

– Psoriasis (thicker crust, very well demarcated)

– Tinea corporis or autoeczematization (prominent tinea pedis, more distal involvement)

35 year old male with itchy hand bumps, noted them shortly after the birth of his son last month (allergic to

diapers!?!)

Dyshydrotic Eczema

• Common manifestation of eczema or irritant dermatitis in adults with or without atopic history

• Lateral aspects of the digits

• “Taapioca pudding balls”

• Very itchy

Dyshydrotic Eczema

• Differential diagnosis-– Tinea manum/pedis

– Contact dermatitis

– Palmo-plantar psoriasis

• Treatment– Dry skin care

– High potency topical CS (lidex)

– Avoidance of irritants…(hand washing)

67 yo female with chronic lower extremity rash, worsening over the past 2 weeks despite treatment

with neosporin

Allergic Contact Dermatitis

• Delayed-type hypersensitivity response

• Clinical Tip offs

– Well demarcated

– Inflamed appearing- can progress to vesicular and then scaly

– Itchy

– Progressively worsening despite use of X

Allergic Contact Dermatitis

• Common clinical scenarios

– Stasis dermatitis “BLE cellulitis”

– Post-op wound care

– “infected” bug bite, scratch, etc.

• Other tip-offs

– Afebrile

– No white count

Allergic Contact Dermatitis

• Diagnostic Gold Standard– Patch testing (Dr. Vince DeLeo)

– Etiology can sometimes be determined with history and distribution

• Treatment– Avoidance of allergen

– Topical Corticosteroids (TAC or lidex)

– Occasional prednisone taper (more frequently for diffuse reaction to poison oak/ivy)- taper for at least 2-3 weeks

Allergic Contact Dermatitis

45 yo female with itchy and red rash under the breasts

“Intertrigo”

• A catch all phrase

• Seen in skin on skin areas- breast, groin, pannus, gluteal cleft, axillary vault, neck folds

• Goal is to try to focus therapy for underlying etiology

“Intertrigo”

• Candida intertrigo

• Tinea corporis

• Inverse psoriasis

• Run of the mill maceration

A hiatus from rashes

30 year old male with

Or more likely…

Verruca

• Treatment options– Staple of therapy

includes paring and liquid nitrogen in the clinic

– Other options include topical efudex/sal acid, intralesional candida or bleomycin, oral cimetidine, laser therapy

Verruca

• Similar response rates for home care– Soak luke warm water 5-

10 minutes

– Nail file/pumice stone (don’t use anywhere else)

– Apply salicylic acid (can also consider efudex or aldara) and occlude

30 year old male with “pimple” that he has had for years, has become tender and red over the past 2 days

Epidermal Inclusion Cyst “EIC”

• Possibly caused by deep penetrating trauma or related to plugging of follicular orifice (acne)

• If not inflamed-compressible but not fluctuant, mobile, often with punctum

Epidermal Inclusion Cyst “EIC”

• When confronted with an inflamed lesion– I&D can help to relieve symptoms, but is not curative (and can lead to

scarring which makes them harder to remove later)

– Rarely requires antibiotics (not truly infected)

– Intra-lesional kenalog can help to resolve symptoms as well

• Long term treatment – Removal of contents and cyst wall

– With nodules that are not inflamed rec’d to patients that they do not manipulate the area- increases risk of inflammation

And because….LAC-USC…a brief detour into derm

emergencies

HPI

• 36 year old male with HIV/AIDS (last CD4 55) presents to the clinic with crusting of his lips, red eyes and a painful rash starting on his body

• First noted that morning

• Meds- HAART, started 1 week ago on bactrim & acyclovir for prophylaxis

• Endorsing subjective fevers

PE

SJS/TEN

• Definition– Severe life threatening reactions that results in necrosis

of the epidermis and sloughing of skin and mucous membranes

– Almost exclusively triggered by a medication

– Many proposed mechanisms

• Presentation– Fevers, prodromal symptoms

– Painful Rash

– Skin sloughing, +Nikolsky sign

– At least 1 mucosal surface is involved

– Generally within 7-21 days of starting medication *

SJS/TEN

• SJS/TEN spectrum – <10% BSA SJS– 10-20% SJS/TEN overlap– >20% TEN

• Because of involvement of the mucous membranes, patients can also experience– Severe dysphagia– Scarring affecting the eyes– Painful urination– Diarrhea related to

sloughing of the gut

SJS/TEN

• Common offenders-

– Allopurinol

– Antibiotics (sulfa)

– Anticonvulsants

– NSAIDS

SJS/TEN

• Clinical Mimickers – Erythroderma (should

not have exposed dermis/+Nikolsky, no mucosal involvement)

– Acute Generalized Exanthematous Pustulosis

– Pustular Psoriasis

– Bullous fixed drug

SJS/TEN

• Treatment – Controversial

• SJS– DISCONTINUE THE MEDICATION– DERMATOLOGY CONSULT (BIOPSY)– SUPPORTIVE CARE

• TEN– DISCONTINUE THE MEDICATION– DERMATOLOGY CONSULT (FROZEN SECTION BIOPSY)– BURN UNIT***– MEDICATION? (CSA, IVIG, TNF alpha INHIBITOR, steroids)

HPI

• 55 year old female who is currently undergoing treatment for fungal sinusitis

• She is complaining of a generalized, itchy rash that started 2 days ago

• Also endorsing subjective fevers and chills

• Current medications include

– Ampicillin daily- started 6 weeks ago

– Fluconazole daily- started 6 weeks ago

– Lisinopril for blood pressure

– As needed (prn) ibuprofen for pain

DRESS

• DRESS – not a classic drug rash– Morbilliform drug rash but….

– 3 weeks after starting a medication (range 1-12 weeks)

– Facial Swelling

– Lymphadenopathy

– Systemic Involvement

– Mortality as high as 10%

DRESS

• Common offenders – Allopurinol– Antibtioics (sulfonamide, PCN, minocycline, metronidazole)– Anti-TB Meds (Isoniazid)– Anticonvulsants (phenytoin, carbamazepine, lamotrigine)– NSAIDS (sulindac, diclofenac, meloxicam)– Anti-HIV Drugs (abacavir)

• Pathophysiology – Not fully understood, may have to do with reactivation of HHV-6

Case 4- DRESS

• ***Systemic Involvement

Chen YC, Chiu HC. Drug Reaction With Eosinophilia and Systemic Symptoms.

Arch Dermatol. 2010;146(12):1373-1379

Case 4- DRESS

• Treatment

– DISCONTINUE ALL POTENTIAL OFFENDERS!!!

– Consult dermatology

– Create a drug timeline

– If no/mild systemic involvement- comfort

– If systemic involvement- slow steroid taper

In summary

Lichen Simplex Chronicus

• Related to chronic rubbing

• Break the itch/scratch cycle

• Treat with high potency topical corticosteroids

Nummular Eczema

• Common on the lower extremities of older individuals

• Itchy and unpleasant

• Good dry skin care

• Moderate potency topical corticosteroids

Dyshydrosis

• Hand eczema

• Tapioca pudding like vesicles

• Dry skin care +potent topical CS

Contact Dermatitis

• Well demarcated, itchy rash

• Can refer for patch testing if unsure of the trigger

• Treat by withdrawing trigger and using topical corticosteroids

Intertrigo

• Consider what is contributing

– Dermatophyte (tineacorporis)

– Candida

– Psoriasis

– Run of the mill maceration

• Treat accordingly

Epidermal Cyst

• Rupture leads to foreign body reaction

• Thankfully they are infrequently infected

• I&D can relieve symptoms but make permanent removal more difficult

• Excision of cyst and cyst wall most effective

Thank you!

Survey

Arico M, Comelli A, Bossi G, et al. Langerhans cell histiocytosis and acute leukemia: unusual association in two cases. Med Pediatr Oncol. 1993; 21(4): 271 – 73.

Aubert-Wastiaux H, Barbarot S, Mechinaud F, et al. Childhood Langerhans cell histiocytosis associated with T cell acute lymphoblastic leukemia. Eur K Dermatol. 2001 Jan-Feb;21(1):109 – 10.

Bolognia J, Jorizzo J, Schaffer J. Dermatology, Third Edition. Mosby Elsevier. 1529 – 1535. Egeler RM, Neglia JP, Puccetti DM, et al. Association of Langerhans Cell Histiocytosis with

Malignant Neoplasms. Cancer. 1993 February; 71 (3): 865 – 72. Egeler RM, Neglia JP, Arico M, et al. Acute leukemia in association with Lagerhans cell

histiocytosis. Med Pediatr Oncol 1994; 23(2):81 – 5. Feldman AL, Berthold F, Arceci RJ, et al. Clonal relationship between precursor T-lymphoblastic

leukaemia/lymphoma and Langerhans-cell histiocytosis. Lancet Oncol. 2005 June; 6: 435 – 37. Imhof B, Aurrand-Lions M. Adhesion mechanisms regulating the migration of monocytes. Nature

Reviews Immunology 4, 432-444 (June 2004) Raj A, Bendon R, Moriarty T, et al. Langerhans cell histiocytosis following childhood acute

lymphoblastic leukemia. Am J of Hematol. 2001 Dec; 68(4):284 – 86.

References