Skin Pathology Laboratory

Dr. Savita Arya MD, DPB, MBBS

Associate Professor, Pathology, Ross University School of Medicine

 A 35-year-old woman has 17 pale tan-to dark brown lesions on her torso and upper extremities. They range from macules to small papules 2-6 mm in diameter. They have smooth borders and uniform pigmentation. The microscopic appearance of one of the lesions is shown. What is your diagnosis? Intradermal Nevus

Dysplastic nevus
Gross
Pigmented macule with variable pigmentation and irregular borders

Biopsy
Melanocytic proliferation with mild architectural and cytologic atypia Lamellar fibrosis

Features
Larger than most acquired nevi In non-sun-exposed areas Risk of developing malignant melanoma Autosomal dominant condition >100 nevi Mutated CDKN2A gene

 A 51-year-old man sees his physician because of growth and change in color of an abdominal mole that, according to his statement, has been present since his birth. The mole has always had an oval shape with even, brown pigmentation. Recently, the patient noticed changes at the edge of the mole. The shape has become irregular, and some areas show dark discoloration. He denies pain or itching. This is the first time that he has seen a physician for this type of complaint.

He has no family history of malignant melanoma.

Clinical presentation
Lesion is irregular in pigmentation and contour, and very suspicious for a malignant melanoma.
D.D. Pigmented lesion 1. Melanocytic lesions Melanocytic nevi, Dysplastic nevi, Malignant melanoma 2. Non-melanocytic lesions Seborrheic keratosis, Basal cell carcinoma, Hemangioma, Kaposi sarcoma

Skin biopsy

Skin, malignant melanoma High power

Hyperchromatic and pleomorphic polygonal and spindle cells; nucleoli prominent; Cytoplasmic melanin granules may be seen

Superficial spreading type

Nodular melanoma

When the melanoma begins the vertical growth phase, metastases are more likely to occur.

 Major risk factor

Exposure to uv light (UVB), inducing pyrimidine dimers

Molecular alteration
Familial melanoma Deletion of P16/INK4a gene encoding for CDKN2 Mutations involving CDK4 and BRAF genes

Prognosis
Depends particularly on depth of invasion
Lesions <0.75 mm deep Good prognosis (>95% 5-yr survival) Lesions > 0.75 mm deep Poor prognosis (<50% 5-yr survival)

 A 55-year-old man sees his physician because of a firm, light brown papule on his back. The lesion is round, has a diameter of 14 mm, and a surface 3 mm above the surrounding skin level. The patient worries that he might have a malignant melanoma. There is no bleeding, itching, or pain.

 Are these lesions benign or malignant? Malignant What would the appearance of many lesions suggest in a patient with an underlying malignancy?
Sign of Leser-Trlat
Occurrence of multiple seborrheic keratoses over a short time Paraneoplastic syndrome

Production of TGF- by malignant cells.

Low-power magnification Thickened epidermis, elevating the lesion above surrounding skin

Thickened (acanthotic) epidermis composed of epithelial cells with scant cytoplasm resembling immature squamous cells of epidermal basal layer (basaloid cells). Small cystlike structures containing lamellated pink keratin present within this proliferation (pseudohorn cysts).

A 67-year-old man comes to the outpatient clinic with a lesion on his left cheek. The nodular lesion measures 12 mm in widest diameter and has a pearly color with clearly visible blood vessels and a small crust on top of it. It has been present for 3 months, and, despite the use of ointments prescribed by the patient's family physician, it has not disappeared. Nearly every morning while the patient is washing his face, the crust comes off and the lesion starts bleeding. Basal Cell carcinoma!

 The family physician finally sends the patient to see a dermatologist with this question: Is this non-resolving lesion a form of skin cancer? The dermatologist suspects basal cell carcinoma and takes a small biopsy specimen from the edge of the lesion. The biopsy results confirm the diagnosis, and the patient subsequently undergoes definitive therapy

The tumor is composed of basaloid cells. The cells forming the periphery of the tumor nodules tend to be arranged radially with their long axes in parallel alignment (palisading). A large cleft is visible

Solitary, 5 mm pearly pink papule with telangiectasias

Rounded nests of basaloid cells

Peripheral palisading

Cleft formation

What are the risks of developing basal cell carcinomas?

Lightly pigmented individuals with sundamaged skin Immunosuppressed patients Inherited defects in DNA nucleotide excision repair (NER) pathway
Xeroderma pigmentosum

Patients with Nevoid basal cell carcinoma syndrome

Gorlin syndrome Germline mutation of PTCH gene, which normally inactivates SMO transmembrane protein upregulating transcription factors

Actinic Keratosis- precursor for cancer

B
A. Cutaneous horn. B. Sandpaper-like plaques. C. Basal cell layer atypia with hyperkeratosis and parakeratosis.

17

Describe the histologic findings

Solar elastosis

Small proliferative buds of cytologically atypical keratinocytes

Parakeratosis

Atypical keratinocytes

Solar elastosis

Scalp, squamous cell carcinoma Clinical presentation

Large actinic keratosis on the balding scalp of an elderly man. In the center, a non-healing ulcer is present consistent with superimposed squamous cell carcinoma.

Skin, squamous cell carcinoma Medium power

Atypical squamous epithelial proliferation in the dermis surrounded by a lymphocytic infiltrate consistent with welldifferentiated squamous cell carcinoma

 Risk factors for squamous cell carcinoma

Sun exposure Immuno-compromised (eg. transplant recipients) Xeroderma pigmentosum Multiple skin tumors; mutation in DNA nucleotide excision repair (NER) genes

 A 55-year-old man requests removal of multiple skin tags around his neck. He is overweight and has diabetes and acanthosis nigricans. While some of his skin tags occasionally get caught on his clothing, he just doesn't like the way they look

Many skin tags and acanthosis nigricans on the neck of a man with diabetes

 Skin tags, on histology, are characterized by acanthotic, flattened, or frond-like epithelium.

Case History
A 30-yr-old woman with recent onset of red, oozing area shown reports that by weeks end it has evolved to raised, scaling plaques. What is your diagnosis?

 Eczema
General term for the acute appearance of red, oozing and crusted lesions that in time become scaling plaques.

Possible causes
Contact dermatitis Atopic dermatitis Insect bite Drug reaction Chemical exposure Photosensitivity

 History of recent hike with some friends in a local wilderness area. The trail was quite overgrown.

Poison ivy (Contact dermatitis)

 A 42-year-old man presents with an intensely itchy and blistering rash. Symptoms began one day before. The rash extends over his arms, hands, chest and face. The lesions are red and vesicular. On further discussion, the patient states that he has experiences these symptoms many times in the past, and attributes the rash to contact with poison ivy. The patient had been doing yard work the day prior to the onset of symptoms.

Microscopic features of the rash

Allergic contact dermatitis (secondary to poison ivy exposure) Epidermis
Spongiosis Lymphocytes

Spongiotic vesicle

 A 25-year-old woman prescribed carbamazepine for a seizure disorder develops a papulo-vesicular skin rash with the microscopic appearance shown. What is the general term for the histologic appearance?

Epidermis shows marked edema with spongiosis Spongiotic vesicles are filled with fluid

 An 18-year-old man visited the dermatologist after developing itchy, scaly, red papules on the skin of his elbows, scalp, and knees over several months. When the scale was lifted from one of the plaques, multiple minute bleeding points became visible.

Skin shows typical well-demarcated plaques covered by silver-white scales.

Biopsy
performed at the edge of one of the lesions confirmed the clinical impression.

Elongated rete ridges Parakeratotic scale Superficial perivascular infiltrate

Micro-abscess of neutrophils within parakeratosis

 Risk factors for psoriasis

Skin trauma (Koebner phenomenon) Emotional stress, cigarette smoking, alcohol consumption, drugs (NSAIDs)

Associated nail changes

Yellow brown discoloration with pitting Separation of nail plate (onycholysis)

Associated joint disease

Psoriatic arthritis distal inter-phalangeal joints of hand and feet involved (similar to RA)

Psoriasis
1. Parakeratosis 2. Thin granular layer 3. Thin supra-papillary epidermis 4. Elongated rete ridges (acanthosis) 5. Blood vessels in papillary dermis 6. Inflammation
36

Psoriasis
Munro microabscesses
Neutrophil aggregates in epidermis

37

 Salient histological features

Acanthosis with thinning of stratum granulsoum Parakeratotic scale Downward elongation of rete ridges Dilated vessels in dermal papillae

What is the pathogenesis?

TH1 immune response Autoimmune reaction of Langerhans cells and CD4+ cells with activation of CD8+ cells and release of cytokines like TNF
Increased rate of keratinocyte replication

 Clinical course
Therapy resulted in partial remission of patient's symptoms. In the following years, the patient developed involvement at other sites including the abdomen and inter-gluteal cleft.

 A 37-year-old woman presents with an itchy rash on her elbows and back since the last few months. Her mother has a history of similar lesions as well as a history of arthritis. On examination, the patient has a 4-cm sharply demarcated plaque on her left elbow. The lesion is scaly and has a silver sheen. A biopsy is performed.

Flat-topped papules Confluent papules Lichen planus presents with pruritic, purple, polygonal papules

A 35-year-old woman who recently returned from Africa presents to the clinic with complaints of a rash. During her trip, she developed an itchy rash on both arms. She has an unremarkable medical history. Medications recently taken include chloroquine for malaria prophylaxis. Examination discloses multiple small violaceous papules on the flexor surfaces of the arms. The lesions have angular borders and flat tops. Some of the lesions have minute white streaks on surface, barely visible to the naked eye.

 Elevated flat-topped appearance of papule

Dense array of lymphocytes in superficial dermis

Wickhams striae Whitish discoloration

Chronic inflammation and hyperkeratosis of cornified layer of epidermis

Biopsy
Mainly lymphocytic inflammatory infiltrate with hyperkeratosis, increased granular layer and liquefaction of basal cell layer

1 2 3 4

1. 2. 3. 4.

Thicker granular layer Acanthosis Saw-tooth rete ridges Lymphoid infiltrate of papillary dermis

Civatte Bodies

 A 35-year-old man treated with cephalosporin for an URTI develops the lesions shown over the extensor surfaces of his extremities, palms, neck and face. They subside in 3 weeks. What is your diagnosis?

 Erythema multiforme
Classic targetoid lesions central pale vesicle surrounded by a zone of erythema. Macules, papules, vesicles, and bullae.

What is the immunological basis for this condition?

Delayed type hypersensitivity reaction typically against an agent that haptenates self proteins and elicits an inflammatory response

What can precede the development of these lesions?

Herpes simplex infection Mycoplasma, many bacteria and fungi Drugs Antibiotics, anticonvulsants, antipyretics, and anti-tuberculous agents Underlying carcinoma or lymphoma Collagen vascular disease - SLE

 A 47-year-old woman treated with sulfonamide for a fever and sore throat develops symmetric erythematous skin lesions on her face and torso 2 days later, which progress to flaccid bullae that slough. Biopsy is shown below. What is your diagnosis?

 TEN

Necrosis of epidermal keratinocytes Separation of epidermis at DEJ Most severe variant of EM Usually associated with prior drug therapy
Mortality rate up to 40%

Steven Johnson syndrome

Mucosal involvement (Oral cavity, conjunctiva, urethra, genital and perianal regions Mortality rate 5%

 A 62-year-old man visits his physician with painful lesions on his soft palate. On inspection, there are multiple red areas of ulceration. The oral lesions prevented the patient from eating normally. A mouthwash is initially prescribed. The lesions do not disappear, and after a few weeks, round to oval vesicles and bullae also appear scattered on the patient's face, chest, and groin.
Axilla shows large areas of ulceration. On the inner side of upper arm, few intact blisters are visible

 A biopsy is performed Immunofluorescence shows immunoglobulin deposition along cell membranes of epidermal keratinocytes in a fishnet-like pattern. Patient is subsequently treated with a combination of corticosteroids and azathioprine resulting in disappearance of his skin lesions.

Blister roof Blister base Acantholytic cells Row of tombstone

Fish netlike pattern

 What does the autoantibody in this disease recognize?

Desmoglein 3 (component of desmosomes that hold keratinocytes together in stratum spinosum

How do blisters form?

Bound antibody on the surface of keratinocytes activates them to release a urokinase-like plasminogen activator (serine protease) that degrades desmosome junctions Epidermal cells lose adhesion --- acantholysis Blister is formed above the basal layer

 An 80-year-old man presents with recent onset of blisters on his legs and arms. Physical examination - Large, tense blisters on medial thighs and flexor aspect of forearm.

Microscopy Direct Immunofluorescence

Blister
Sub-epidermal Roof Intact, entire epidermis (including stratum basalis) Content- Inflammatory cells, fibrin, fluid

Linear deposition of IgG along dermo-epidermal junction

Edematous papillary dermis

 What is the immune mechanism involved?

IgG autoantibodies are directed against hemidesmosome proteins at the DEJ (eg. BPAg2 type XVII collagen, a transmembranous protein with a collagenous extracellular domain)

How do the bullae form?

Immune-mediated BM damage (via complement activation and through the activity of Fc receptorbearing inflammatory cells) leads to hemidesmosome degradation and subepidermal separation.

THANK YOU!
References
Kumar: Robbins and Cotran Pathologic Basis of Disease, 8th ed., Elselvier Saunders Company, 2010 Rubin R, Strayer DS. Rubins Pathology: Clinico-pathologic Foundations of Medicine, 5th edition, Lippincott Williams & Wilkins, 2008 Webpath.: The Internet Pathology Laboratory for Pathology Education.