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Tammie Ferringer, MDGeisinger Medical Center

Depts of Dermatology and Pathologytferringer@geisinger.edu

Essentials in Metabolic Disease Involving the Skin

I do not have any relevant relationships with industry

Case 1

79 year old female with non-healing tumor versus ruptured mucocele on left lower lip

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Diagnosis?

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ELASTOSIS PERFORANS SERPIGINOSA

EPS

EPS Associated Disorders

Rothmund-Thomson syndrome

Acrogeria

Penicillamine therapy

Marfan syndrome

Osteogenesis imperfecta

PXE

Ehlers-Danlos syndrome

Down syndrome

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Penicillamine

◼ Chelating agent

◼ Used to treat Wilson’s disease, RA, lead or mercury poisoning

◼ Effects elastin cross-linking via inhibition of copper-dependent lysyl oxidase

◼ Thorny appearing elastic fibers

◼ Systemic elastolytic process

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Case 1: Penicillamine Induced EPS

◼ Diagnosed with Wilson’s disease over 50 years ago

◼ Treated with penicillamine

Wilson’s Disease

◼ AR disorder of copper metabolism

◼ Accumulation of copper in liver, brain, cornea and other organs

Manifestations of Dermal Elastic Tissue Change Due To Penicillamine

Pseudo-PXE

Acquired Cutis LaxaAnetoderma

EPS

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Case 1

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Differential DiagnosisInherited PXE

VVG

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Von Kossa

Von Kossa

◼Lipodermatosclerosis

◼Morphea profunda

◼Erythema nodosum

◼BCC

◼GA

◼Lichen sclerosus

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PXE-Like Changes

PXE-Like Changes

PXE-Like Changes

Von Kossa

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Calciphylaxis with PXE change

PXE-Like Changes

MM re-excision with PXE Change

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PXE-Like Changes 64yo female with rash on the right lower lateral leg that

flares with redness, pustules, and erythema

Fungal Folliculitis with PXE Change

Take Home for Catnappers

◼ Penicillamine induced elastic fiber changes resemble bramble bush and do not calcify like PXE

◼ EPS occurs in “RAPMOPED”

◼ PXE-like changes can be seen in other inflammatory processes: calciphylaxis, erythema nodosum, lipodermatosclerosis, morphea profunda

◼ Rothmund-Thomson syndrome

◼ Acrogeria

◼ Penicillamine therapy

◼ Marfan syndrome

◼ Osteogenesis imperfecta

◼ PXE

◼ Ehlers-Danlos syndrome

◼ Down syndrome

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Case 2

11/13/13

55 yo hospitalized patient s/p MVA complicated by multiple abdominal surgeries

◼Chest biopsy: Suppurative folliculitis with pityrospora

◼Treated with fluoconazole, doxycycline, and ketoconazole wash

12/2/13

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Left dorsal hand

Diagnosis?

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Nutritional Deficiency

◼ Zn 7 mcg/dL nl (60-130)

◼ Was receiving 1.3 mg/d of zinc in his TPN

◼ 3 mg/d is required in patients without GI losses, and up to 12 mg/d in patients with diarrhea or fistula losses

◼ Improved rapidly following additional zinc supplementation

12/11/13

• Acrodermatitis enteropathica• AR altered zinc metabolism

• Acquired AE • Infants on formula• Alcoholics• Malabsorption syndromes• Limited supply of injectable zinc in the US resulting in

several cases of zinc deficiency in those receiving TPN

Zinc Deficiency

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Take Two s/p small bowel resection due to SMA occlusion

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Zinc (60-130mcg/dL): 1347

Patient #1

Nutritional DeficiencyPellagra

◼ Niacin deficiency

◼ 3 D’s: Diarrhea, Dementia and a collar-like Dermatitis (Casal’s necklace)

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Nutritional DeficiencyNecrolytic Migratory Erythema

◼ Glucagon-secreting tumor of the pancreas

◼ Periorificial, flexural, intertriginous, and acral

◼ Circinate erythematous patches to plaques with necrosis, erosion, and crusting

◼ Red shiny erosive fingertips

◼ Weight loss, beefy-red tongue, angular cheilitis

Take Home◼ Nutritional Deficiency

◼ Pallor of the superficial epidermis with or without necrosis

◼ Confluent parakeratosis and psoriasiform epidermal hyperplasia

◼ Zinc Deficiency ◼ Acral and periorifical pustulobullous dermatitis, pustular

paronychia, angular stomatitis, diarrhea and alopecia

◼ Early can present with pustular folliculitis

Case 331 year old female with mass on the left forehead for 2

months

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Diagnosis?

S100

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CD68

CD68

PAS

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Crystal-Storing Histiocytosis

◼ Intracellular accumulation of crystallized immunoglobulins

◼ Localized cutaneous form and generalized variant

◼ Strong association with lymphoplasmacytic neoplasms expressing immunoglobulin kappa light chain

◼ Multiple myeloma>lymphoplasmacytic lymphoma>MGUS> extranodal marginal zone lymphoma

◼ Cutaneous involvement of head and neck, especially eye/orbit

◼ Cutaneous involvement may precede hematologic process

Cutaneous Crystal-Storing Histiocytosis

◼ Dermal or subcutaneous sheets of macrophages with shards of eosinophilic crystals

◼ Variable PAS

◼ Non-birefringent

JAAD 2017:77:1145-58.

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Kappa LambdaCase 3

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Case 4

68yo male with history of multiple myeloma, acute

renal failure requiring

hemodialysis and a painful rash on bilateral soles and

palms x 3wks

Courtesy Doina Ivan, MD of M. D. Anderson Cancer Center, TX

Diagnosis?

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Crystalglobulinemia

◼ AKA cryocrystalglobulinemia

◼ Paraneoplastic syndrome associated with multiple myeloma, B-cell CLL, other B-cell malignancies

◼ Purpuric petechial rash with necrotic ulcers and hemorrhagic blisters, especially of distal extremities

◼ Systemic involvement including kidney, lung, GI, and CNS

◼ Type of type I cryoglobulinemia

◼ Pauci-inflammatory with fibrin thrombi (thrombotic microangiopathy)

◼ Non-refringent crystals, composed of monoclonal immunoglobulins

Crystalglobulinemia

Victoria AL, Cerroni L, Kutzner H, Requena L. JAAD 2017;77:1145-58.

Type of Cryoglobulinemia (Type I)

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Crystalglobulinemia: Multiple myeloma presenting with cutaneous and neurological manifestations

Australasian Journal of Dermatology, 1 AUG 2017

Take Home

◼ Modified immunoglobulin deposition can result in crystal storing histiocytosis, crystalglobulinemia, in addition to amyloid

◼ Pauci-inflammatory with fibrin thrombi: embolic (cholesterol, metastases, infectious, myxoma…), coagulopathy, calciphylaxis

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Case 5

71 yo male with hand dermatitis and nail

dystrophy

Case 571 yo male with hand dermatitis with

hemorrhagic bullae and rare milia

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Biopsy:

A. Dorsal left lateral finger

B. Dorsal left lateral finger (submitted for DIF)

Clinical history: Bilateral palms/all fingernails with generalized xerosis, lichenification and scale with a few <=1 cm hemorrhagic tense bullae or various stages of healing and a few milia on dorsal hands. Xerosis and fissures of all proximal nail folds, all fingernails splitting/dystrophy.

Preop Dx: Hand dermatitis with traumatic bullae vs PCT vs EBA

Case 5

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CK903

Diagnosis?

Keratin Derived AmyloidLichen Amyloid

◼ Pruritic small hyperpigmented papules

◼ Anterior shins

Macular Amyloid

◼ Mottled hyperpigmentation

◼ Interscapular area

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Keratin Derived Amyloid

Lichen

**Hyperkeratosis and acanthosis

Macular Amyloid

Pink amorphous deposit in the papillary dermis with melanophages

DDx of ”normal” skinMnemonic

Ichthyosis vulgaris

Vitiligo

Argyria

Candida

Urticaria

Urticaria Pigmentosa (espTMEP)

Macular Amyloid

Dermatophyte

Onchocerciasis (microfilaria)

Gold (chrysiasis)

PXE and Psoriasis (guttate)

Ulerythema ophryogenes

Seb derm and Scleredema

Stratum corneum Candida, Tinea, Guttate psoriasis,

Seb derm

Granular layerIchthyosis vulgaris

Basal layer- Vitiligo

Dermal papillaeKeratin derived amyloid

DermisTMEP, Onchocerciasis, Urticaria, Gold,

PXE, Scleredema, CTN

Eccrine- Argyria

Clinical type of amyloidosis

Amyloid fibril protein

Precursor substance

Localized cutaneous

Primary

Macular amyloidosis

Altered keratin

Keratin

Lichen amyloidosis Altered keratin

Keratin

Nodular amyloidosis

AL Ig light chain

Secondary

Cutaneous tumors Altered keratin

Keratin

Localized Cutaneous Amyloid

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Thioflavin-T

Nodular Amyloid

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Case 5

Case 5

Biopsy (3-27-14):

A. Right 5th lateral finger

B. Right 5th lateral finger (submitted for DIF)

Clinical history: Bilateral hands show tense bullae on dorsal hands and fingers, coming and going x 1 year, healing with scars and contractures; also lips at times have tiny vesicles at commissures, ptis iron deficient/anemic, positive ANA 320.

Preop Dx: PCT, pseudo PCT, bullous LE, EBA, doubt BP|

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|

| 92Amyloid P

Case 5

Amyloid A

Case 5

| Kappa Lambda

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Case 5

Biopsy

A. Abdominal fat pad

Clinical history: Bullous and hemorrhagic lesions on hands and lips x months, systemic workup ongoing

Preop Dx: R/O amyloidosis.

Case 5: Lambda restricted Multiple Myeloma with Amyloidosis

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Primary Systemic Amyloid

◼ +/- Multiple myeloma

◼ Nodular amyloid

◼ Macroglossia

◼ Pinch purpura

◼ Blind abdominal fat or salivary gland biopsy

Amyloid

◼ Thioflavin-T

◼ Yellow to yellow-green with fluorescent scope

◼ Other Amyloid stains:

◼ Congo Red

◼ Crystal violet

◼ Cotton dye (Pagoda Red)

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Amyloid: Apple Green with polarized light

Clinical type of amyloidosis Amyloid fibril protein

Precursor substance

Systemic

Primary/myeloma-associated AL Ig light chain

Secondary AA Serum amyloid A

Familial Mediterranean Fever AA Serum amyloid A

Muckle-Wells Syndrome AA Serum amyloid A

Familial Amyloid Polyneuropathy

Prealbumin(transthyretin)

Hemodialysis-associated B2-microglobulin

Systemic Amyloid

• Received: abdominal fat pad biopsy

• Clinical History: “history of melanoma, ?amyloid”

46 year old female

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• IHC for Amyloid P: positive• IHC for Amyloid A and transthyretin: negative

Additional History • Enlarged tongue

• History of peripartum cardiomyopathy

• Multiple myeloma

• Dialysis dependent CRF

• Peripheral neuropathy

• DM

• Sent to Mayo for mass spec

Insulin Antibody

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Insulin-Derived Amyloid Tumor• Firm mass ranging from 1-7 cm

• Localized to site of repeated injection

• Broad range of insulin types

• Middle-aged to elderly type I diabetic males

• Amorphous pink deposits with FBGCs

• Not associated with systemic amyloidosis

Take Home

◼ Modified immunoglobulin deposition can result in crystal storing histiocytosis, crystalglobulinemia, in addition to amyloid

• Amyloid fibrils are formed by partial proteolysis of various precursor proteins that form beta-pleated sheet (AA, AL, beta2-macroglobulin, insulin)

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Case 6

76yo female with CKD, PVD, Afib,

urosepsis with purpuric rash on lower legs

DDx: vasculitis,

vasculopathy, infectious,

other

Von Kossa

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Diagnosis?

Case 6: Calciphylaxis

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(Am J Dermatopathol 2013;35:582–586

◼ No special stains used to evaluate for perieccrinecalcifications

AJDP 2017;39:795-802.

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Take Home

◼ Calciphylaxis

◼ Check Von Kossa

◼ Potential clues

◼ Calcified PXE-like elastic fibers

◼ Eccrine calcifications

◼ Extravascular calcification

◼ Dermal angioplasia

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Thank You