PowerPoint Presentation

Skin anatomy and dermatopathology

Christian Rose

Dermatopathology Laboratory Lübeck

56,284 cases in the year 2017

48% are melanocytic tumors, mostly nevi

34% epithelial neoplasms (appr. 70 cases per day)

10% soft tissue lesions

5% inflammatory disease

3% others (e.g. cytes)

1st edition 1974 4 authors 3 countries

2th edition 1996 14 authors 10 countries

4th edition 2018 183 authors 24 countries

3th edition 2006 150 authors 20 countries

J Am Acad Dermatol 2005, 52: 101-8

- Histopathological characteristics of lethal NMCS during a 5-years period

120 deaths, median age of deaths was 79 years

• 89 squamous cell carcinoma • 22 Merkel cell carcinoma • 9 others (6 sarcomas, 3 adnexal neoplasms)

PAS stain

Penetration depth of ultraviolet light

UVB

UVA

p53 expression

The prevalence of somatic mutations across human cancer types

Signatures of mutational processes in human cancer Alexandrov LB et al. Nature 2013, 500: 415-421

Actinic keratosis

Actinic keratosis ctinic keratosis

Actinic keratosis

Field canceration

Structure of the basement membrane zone

Desmoglein 1

Keratinfilamente

Desmoglein 3

Desmocollin 1

Plectin

BP230

BASALE KERATINOYT

BP180/ Typ XVII Kollagen

b 4 Kette

a6b 4 Integrin

a 6 Kette

p200

Plecti n

LAMINA LUCIDA

Laminin 5

Laminin 5

LAMINA DENSA

SUBLAMINA DENSA

Typ VII Kollagen

Typ VII Kollagen

12-year-old girl under the eyelid

Basal cell carcinoma

8-year-old boy Le Sueur et al. Arch Dermatol 2000,136: 370

7-year-old boy, for 1 year Griffin et al. JAAD 2007; 57: S97

10-year-old boy, for 4 months Baum, Hog. Hautarzt 1994, 45: 406

Basal cell carcinoma in childhood: case report and literature review Griffin et al. J Am Acad Dermatol 2007; 57: S97-102

• 107 children, boys and girls equally affected • Mostly on the head (90%) • 20% recurrence rate at follow-up from 4 months to 20 years

Pigmented basal cell carcinoma

J Am Acad Dermatol 1990; 23: 1118-26

Nedved D et al. J Cutan Pathol 2014; 41: 9-13

- 100 basal cell carcinomas

- 6 dermatopathologists subtyped in a blinded fashion

Histological subtypes of BCC stratified by risk of recurrence

Lower risk

Higher risk

Nodular BCC

Basosquamous carcinoma

Superficial BCC

Sclerosing/morphoeic BCC

Pigmented BCC

Infiltrating BCC

Infundibulocytic BCC

Micronodular BCC

Fibroepithelial BCC

Fibroepithelial basal cell carcinoma (Fibroepithelioma of Pinkus)

Degree of cytological differentiation (Grading)

well-differentiated (G1)

moderately differentiated (G2)

poorly differentiated (G3)

Immunhistochemistry Cytokeratin

Perineural invasion

Perineural invasion

Lancet Oncol 2008, 9: 713-20

Tt < 2mm = 0% Tt 2,1 - 6mm = 4% Tt > 6mm = 15%

Definition of cSCC Tumor (T) Staging in AJCC-7

Definition of cSCC Tumor (T) Staging in AJCC-8

Brigham and Women ´ s Hospital tumor staging system (2013) based on 2074 cSCCs

• Tumor diameter > 2 cm • poorly differentiated histology • perineural invasion > 0.1 mm

• Tumor invasion beyond the subcutaneous fat (excluding bone invasion which automatically upgrades tumor to stage T3)

Bowen disease (Squamous cell carcinoma in situ)

Bow

Merkel cell carcinoma

Merkel cell carcinoma

Cytokeratin 20

Cytokeratin 20

Arch Dermatol 1972; 105: 107-10

Immunhistochemistry of T large antigen

Br J Dermatol 2015; 173: 42-49

Task of the dermatopathologist

• clear diagnosis with use of the WHO classification

• provide T stage of recent TNM/AJCC system

• mention other risk factors and particularities

Modern dermato-oncology

Alessandro Di Stefani

Institute of Dermatology Fondazione Policlinico Universitario A. Gemelli, IRCCS Catholic Univesrity of the Sacred Heart, Rome

“…We are beginning to move away from clinico-pathologic diagnosis into an era of clinico-imaging diagnosis…” Biotechnology succeeds in revolutionizing medical science

Diagnostic armamentarium

• Clinical examination

• Total body photography • Dermoscopy

• Reflectance Confocal Microscopy

• New diagnostic technologies: ➢ MelaFind, SIAscope, … ➢

Electrical impedance spectroscopy, OCT, … ➢ Teledermatology, smartphone apps, …

The Dermatologist’s sthetoscope

Nowadays, it is becoming undoubtedly clear that any physician who accepts the responsibility for the examination and the differential diagnosis of skin lesions needs to use dermoscopy

Dermatoscope

Videodermatoscope

Fotodermatoscope digital

The significance of dermoscopy

• Clinical examination alone has 65-80% sensitivity in the diagnosis of melanoma • The results of recent meta- analyses have been demonstrated that dermoscopy improves diagnostic accuracy of melanoma up to 35% compared with naked eye

Why perform dermoscopy?

• Improvement of diagnostic accuracy • Decrease of needless biopsies: ➢ a 42% reduction in the number of patients referred for biopsy ➢ significant reduction in the benign/malignant ratio of excised melanocytic lesions:

▪

from 18:1 (pre-dermoscopy era)

▪

to 4:1 (post-dermoscopy era)

➢

Economic issues: cost-saving for health systems

Menzies S. and Zalaudek I. Arch Dermatol 2006;146:1211-1212

Carli P. et al. Br J Dermatol . 2004;150:687-692

Experience is crucial

• This diagnostic

improvement can be achieved only if the observer has a good degree of experience in the technique • For untrained or less experienced examiners the diagnostic accuracy can decrease as compared to clinical examination

Kittler H, et al. Lancet Oncol 2002;3:159-165

Dermoscopic Diagnosis

• The morphologic diagnosis of pigmented skin lesions is based on the recognition of particular dermoscopic criteria • Each of this criteria has a correspondent histopathological substrate • This is due to distinct alterations of the epidermis, the dermoepidermal junction, and the papillary dermis

Clinico-Dermoscopic-Pathologic Correlation

Histology Vetical plane

Dermoscopy Horizontal plane

Clinical exame Horizontal plane

Pattern Analysis

Histologic Diagnosis of Inflammatory Skin Diseases: A Method by Pattern Analysis

A. Bernard Ackerman

Lea & Febiger (October 1978)

(1936-2008)

Pattern Analysis

Basic histologic patterns

Pattern Analysis

In vivo epiluminescence microscopy of pigmented

Histologic Diagnosis of Inflammatory Skin Diseases: A Method by Pattern Analysis

skin lesions.

Pattern analysis of pigmented skin lesions

Basic histologic patterns

Basic dermoscopic patterns

Pehamberger H et al. J Am Acad Dermatol 1987;17:571-

Pattern Analysis

Dermoscopic Criteria

Global Patterns

Local Features

Reticular

Pigment Network

Globular

Dots/Globules

Cobblestone

Streaks

Homogeneous

Blue-whitish veil

Starburst

Blotches

Parallel

Hypopigmentation

Multicomponent

Regression structures

Lacunar

Vascular structures

Aspecific

Other criteria

Gray

Brown

Blue

Black

Yellow

White it

Red

Blue

Dermoscopy in general dermatology

• The latest generations of commercially available hand-held dermatoscopes are practical and

inexpensive

• With the use of cross-polarized light they do not require direct physical contact between the

optical lens and the skin

• In this way, they can be better employed to investigate vascular structures.

Reflectance Confocal Microscopy

• RCM is a non-invasive imaging technique that uses a near infrared laser beam (830 nm) • images are created from the difference in reflectivity of different tissue structures • Melanin is strongly reflective, keratin

• RCM produces horizontal black and white images of the skin from the surface to the papillary dermis (maximum depth of approximately 250 μm) at a cellular-level resolution Reflectance Confocal Microscopy

Non-melanoma skin cancer (NMSC)

BCC

SCC

AK

ACTINIC KERATOSIS (AK)

Definition A common intraepidermal neoplasm of sun-damaged skin characterized by variable atypia of keratinocytes.

Synonyms Solar keratosis

Weedon D, Marks R, Kao GF, Harwood CA. Keratinocytic tumours. In: LeBoit PE, Burg G, Weedon D, Sarasain A, editors . World Health Organization Classification of Tumours . Pathology and Genetics of Skin Tumours. Lyon: IARC Press; 2006. p. 10-47.

AK – Clinical aspects

• Ill-defined macule, papule or plaque with color ranging from skin-colored to pink to red to brown, with dry, adherent scales. • Solitary or, more frequently, multiple, and the individual size may vary from few millimeters to 1–2 centimeters. • Preferential sites: face, ears, neck, bald scalp, extensor surface of the extremities • AKs are usually asymptomatic although some patients report itching, burning or a splinter-

Actinic keratosis (AK)

AK – Clinical variants

• Hypertrophic • Pigmented • Atrophic • Lichenoid • Actinic keilitis

AK – Clinical aspects

• Pigmented AKs (PAK) • DD: LM, SK • Biopsy

Actinic Cheilitis

• Red papules or plaques well demarcated • Biopsy to rule out iSCC

NATURAL HISTORY OF AK

Spontaneous regression

NO significant changes (remains stable)

Progression to invasive SCC

• Progression rates per lesion/year: 0%-0.075% (0.53% in patients with history of NMSC) • Regression rate per lesion/year (15%-63% after 1y) with recurrent rates (15%-53%) • Variations re counting of AK in time: -53% - + 99.1% • Spontaneous remission in the field cancerization (0% - 21%) with recurrence (57%) Review of 24 studies which have evaluated the natural history of AK ( Presence/absence of immunosuppression and/or history of NMSC)

AK - Natural History

• Difficult to estimate the probability of AK to progress to invasive SCC • SCC in 6%-10% of immunocompetent patients with AK - in 40% of immunosuppresed patients • Risk of invasive SCC from a specific AK is highly variable (<1/1000 – 1.4%) • 60-80% of SCC originates from AK (length of time to progression: 2y)

Rigel e Stein Gold, JAAD 2013;68:S20-7

AK- clinical classification for grading

AK I

AK II

AK III

Palpable reddish-brown, scaly lesion

Erythematous macules ( better felt than seen )

Reddish-brown indurated plaque with an hyperkeratotic surface

AK- clinical classification for grading

AK I

AK II

AK III Reddish-brown indurated plaque with an hyperkeratotic surface

Erythematous macules (better felt than seen)

Palpable reddish- brown, scaly lesion

G. Goldenberg; JEADV 2017

• There is no correspondence between clinical and histological classification • A higher degree of hyperkeratosis is not related to a greater propensity to progression • It is not possible to predict which injury will progress to iSCC

Schmitz et al; JEADV 2016

Advanced SCC

In situ SCC

AK

Early AK

AK III

AK I

AK II

Where does AK end and SCC begins clinically?

Where does AK end and SCC begin dermoscopically?

Strawberry pattern:

• erythema, revealing a marked pink-to-red ‘pseudo-network’ surrounding the hair follicles • white-to-yellow surface scale, • fine, linear-wavy vessels surrounding the hair follicles • hair follicle openings filled with yellowish keratotic plugs and/or surrounded by a white halo • scales

Courtesy of Saturnino Gasparini

AK

✓ Pseudoreticolo rosso-rosa

✓ Superficie con squame

✓ Vasi lineari-ondulati

✓ Tappi cheratotici follicolari

✓ Alone biancastro attorno gli osti follicolari

Pigmented AK or LM ?

Courtesy of Saturnino Gaspari

Courtesy of Saturnino Gaspari

RCM: Confocal Grading of AK

• Parakeratosis and Scales in stratum corneum • Irregular (atypical) honeycomb pattern in basal and spinous layer • Round blood vessels in the papillae

RCM limitations

• Depth of investigation (250 μ m) • Ulcerated lesions • Body site

1. Definition of cSCC

• Cutaneous squamous cell carcinoma (cSCC) is a NonMelanomaSkinCancer (NMSC)

• NMSC are approximately 90% or more of all skin malignancies

• cSCC is one of the most common cancers, accounting for 20% of all NMSC

• cSCC is characterised by the malignant proliferation of keratinising cells of the epidermis or its appendages; in which the component cells show variable squamous differentation

Alam M, et al. J Am Acad Dermatol. 2018 Stratigos A, et al. Eur J Cancer. 2015

Cutaneous Squamous Cell Carcinoma

Clinical types • Superficial • Ulcerative • Vegetant

Motaparthi K, et al. Adv Anat Pathol. 201

Clinical spectrum of cSCC

Inadequate therapy Aggressive behavior Immunosuppression Neglected lesions

Advanced or metastatic disease

Early disease

Diagnostic path

• CLINICAL ASPECTS Anamnesis, Physical examination (complete skin exam)

• NON INVASIVE DIAGNOSTIC TOOLS

DERMOSCOPY

CONFOCAL

• HISTOLOGICAL EXAMINATION

• Instrumental investigations (extensive disease) (bone involvement, perineural invasion, deep soft tissue involvement, eye-orbit)

Skin examination

• Inspection (full body area) • Palpation (lymphnodes) • History of the lesion • Comorbidities and drugs

Carcinoma cuniculatum

Morbo di Bowen (SCC in situ)

❖ Elderly ❖ Sites  legs and trunk ❖ Erythematous patch with scales ❖ Slow growth

cSCC – predominant dermoscopic patterns

VASCULAR

Absent vessels Monomorphic Polymorphic

- Scales/ Keratin plaque

-Vascular pattern

- Ulceration

Diffuse Central Peripheral Clustered

- Bleeding

-Vessel arrangement

- Pinkish areas

Dotted (Rosette) Hairpin Linear irregular

-Vessel morphology

WHITE STRUCTURES

OTHERS

-White circles

- Predominant colour

-White structureless zones

- Grade of pigmentation

- White halos

Rosendahl C, et al. Arch Dermatol. 2012

Scales/keratin plug

Lallas A., et al. BJD 201

White circles

Lallas A., et al. BJD 2015

Vascular pattern

Lallas A., et al. BJD 201

➢ Well differentiated(G1-G2):

- Scales/keratin - White circles - White halos - White structureless areas - Predominant color = White

➢

WHITE predominant color and esophitic lesions

➢ Poorly differentiated (G3-G4):

➢

RED predominant color and flat lesions

- >50% vascularity - Vessel (diffuse distribution) - Bleeding and small vessels - Predominant color = Red

Differential Diagnosis

cSCC

AMELANOTIC MELANOMA

✓ polimorfic/atypical vascolar pattern

Scales

Structureless white areas

DD

cSCC

PIGMENTED Seborrheic K.

✓ Pigmented atypical pattern ✓ Hairpin vessels ✓ Scales

Irregular vascular pattern

♀ 63 aa; arto inf

BCC: CLINICAL FEATURES

• The clinical presentation of BCC can be extremely protean • it may appear as a papulo-nodular lesion with a pearly border, a cystic nodule, an ulcerated destructive lesion, an erythematous plaque with visible telangiectasia, or a whitish indurated plaque

Di Stefani A, Chimenti S. G Ital Dermatol Venereol.

BCC: CLINICAL FEATURES

• many clinical variants have been described: • such as nodular, ulcerative, superficial, morpheiform, pigmented, and fibroepithelioma of Pinkus • linear and polypoid forms; giant lesions • wild-fire type

Di Stefani A, Chimenti S. G Ital Dermatol Venereol.

Basal cell carcinoma (BCC)

• Most common human cancer 1 • Incidence: >1000/100000 in Australia; 1/100000 in Africa; 560/100000 in US • Incidence is increasing worldwide by up to 10% 2 • Average age at presentation: 60 years 3 • 80% occur in the head and neck region 4 • Locally aggressive, infiltrating cartilaginous and bone structures 3

1. Telfer NR, et al. Br J Dermatol 2008;150:35–48 2. Cigna E, et al. J Skin Cancer 2011; doi:10.1155/2011/476362 3. Hauschild A, J Dtsch Dermatol Ges 2008; Suppl1:S2–S4

4. Wong CSM, BMJ 2003; 327:794–798 Image provided by Prof. Ketty Peris

BCC superficiale

• Pink-red plaque, well- defined margins, slow growth • Scales and erosions • Site: trunk

1. Dandurand M. Eur J Dermatol 2006;16:394–401

Superficial BCC

Nodular BCC • A smooth, translucent, greyish papule or nodule with telangiectasia 1 • Pearly border 1 • Slow growth with central ulceration, pigment • Site: head/neck region

1. Dandurand M. Eur J Dermatol 2006;16:394–401

Image provided by Prof. Ketty Peris

F, 79 anni

BCC variants with aggressive behaviour • Morphoeic • Micronodular • Infiltrative • Basosquamous

INFILTRATIVE

SCLEROSING/MORPHEAFORM

BASOSQUAMOUS

Invasion and destruction of surrounding and underlying tissues

Telfer NR, et al. Br J Dermatol 2008;150:35–48

BCC: clinico-pathological correlation

• Different clinical forms may correlate to different histological variants, • the exact clinicopathological correspondence is not easy to achieve on the basis of clinical examination alone • Dermoscopy and Reflectance Confocal Microscopy can reliably help in diagnosing and classifying different BCC subtypes

Di Stefani A, Chimenti S. Basal cell carcinoma: clinical and pathological features. G Ital Dermatol Venereol. 2015;150(4):385-91

BCC: typical dermoscopic features

• Presence of arborizing (treelike) telangiectasia, leaf-like areas, large blue/gray ovoid nests, multiple blue/gray globules, spoke-wheel areas and ulceration

arborizing teleangectasias

blue-gray ovoid nests

leaf-like areas spoke-wheel areas L f-lik areas

ulceration

blue-gray globules

➢ Classic BCC patterns → 95,7% (583/609) ▪ Ulceration ▪ Large Blue/gray ovoid nests ▪ Multiple blue/gray globules ▪ Leaflike areas ▪ Spoke-wheel areas ▪ Arborizing teleangectasias ➢ Melanocytic patterns → 40,6% (247/609) ▪ Multiple brown to black dots/globules ▪ Blue/white veillike structures ▪ Pigmented network ▪ Multiple blue/gray dots (peppering-like) ▪ Radial streaming or pseudopods ➢ Non classic BCC patterns → 26,1% (159/609) ▪ short fine superficial teleangectasia

▪ multiple small erosions ▪ concentric structures ▪ multiple in-focus blue/gray dots

Superficial BCC v s

nodular BCC

Blue/gray color –

Brown color –

Large Blue/gray ovoid nests

Leaf-like areas

– Spoke wheel areas Multiple small erosions Short fine teleangectasias

Ulceration Arborizing

teleangectasias

Superficial BCC v s

nodular BCC

Brown color –

Blue/gray color –

Leaf-like areas

Large Blue/gray ovoid nests

– Spoke wheel areas Multiple small erosions Short fine teleangectasia

Ulceration Arborizing

teleangectasias

Histopathological high risk variants

Infiltrative

Pattern of growth:

Morpheifor

m Micronodul ar

• Infiltrative • Morpheiform • Micronodular

Basosquam ous

Differentiation:

• Basosquamous

Slater D and Walsh M. Dataset for the histological reporting of basal cell carcinoma (2 nd edition). London: The Royal College of Pathologist 2012:1-27.

✓ BSC appears to have overlapping dermoscopic features of BCC and invasive SCC ✓ detection of at least one dermoscopic criterion of both BCC and SCC should raise suspicion for the tumour. • white structureless areas (73%) • superficial scale (68%), ulceration (68%) • white structures (64%) • blue-grey blotches (59%) • blood spots in keratin masses (55%) • unfocused (peripheral) arborizing vessels (73%) • keratin masses (73%)

➢ Classic BCC patterns → 95,7% (583/609) ▪ Ulceration ▪ Large Blue/gray ovoid nests ▪ Multiple blue/gray globules ▪ Leaflike areas ▪ Spoke-wheel areas ▪ Arborizing teleangectasias ➢ Melanocytic patterns → 40,6% (247/609) ▪ Multiple brown to black dots/globules ▪ Blue/white veillike structures ▪ Pigmented network ▪ Multiple blue/gray dots (peppering-like) ▪ Radial streaming or pseudopods ➢ Non classic BCC patterns → 26,1% (159/609) ▪ short fine superficial teleangectasia

▪ multiple small erosions ▪ concentric structures ▪ multiple in-focus blue/gray dots

RCM

Superficial BCC

bright tumoral islands

• • •

Clefting

Dendritic cells

RCM

Nodular BCC

Dark tumoral islands (>300 µm)

• • •

Clefting Vessels

JAAD 2014;71:716-24

BCC – Differential Diagnosis

• Nevus • Melanoma • Keratoacanthoma • Mollusco contagioso • Pigmented seborrheic keratosis

Nodular BCC

Ulcerated BCC

SCC

❑

Morbus Bowen

➢

Psoriasis

➢

Superficial BCC

AK

➢

➢ Lichen planus-like keratosis

Scar

BCC morfeiform

❖

Delay diagnosis

• Elderly • Low socio-economic level • Remote area • Low awareness of skin tumors • Wrong diagnosis

Locally advanced BCC

Role of imaging in diagnosis, treatment and follow-up

Anysja Zuchora University Hospital Galway Medical Physics and Bioengineenering Department Ireland

•

CT / computed tomography

•

MRI / magnetic resonance

• SPECT-CT/ Single Photon Emission Tomografy + CT fusion • PET/ positron emission tomography radiolabel 18-fluorodeoxyglucose (18-FDG) • HFUS / High-Frequency ultrasonography • Dermatoscopy • Optical coherence tomography • Reflectance confocal microscopy

SCC- Squamous Cell carcinoma BCC -Basal Cell Carcinoma

SCC

BCC

¤ Locally aggressive ¤ Potential lymph node involvement ¤ Distant metastasis

¤ Rarely metastatic ¤ Tumours can infiltrate critical anatomic structures / orbit/ or bone and soft tissues ¤ High rate of skin recurrence ¤ Perineural invasion (1-6%)

¤ Perineural invasion (5-14%) ¤ Lymphovascular invasion ¤ Anatomic site /ears, lips, anogenital regions/ ¤ Cranial nerve involvment

MCC- Merkel cell carcinoma DFSP- Dermatofibrosarcoma protuberans

MCC

DFSP

¤ High rate of nodal and distant metastasis ¤ Micrometastatic disease is difficult to detect ¤ Sentinel lymph node biopsy and Elective lymph node dissection

¤ Deeply infiltrating can make tumour extend difficult to predict /H&N ¤ Invade skeletal muscle