Unusual Causes of Leg Ulcerations

John R. Bartholomew, MD, MSVM, FACC

Section Head - Vascular Medicine

Professor of Medicine - Cleveland Clinic Lerner College of Medicine

Cleveland Clinic

I have no financial disclosures related to this talk

Differential Diagnosis for Leg Ulcers

Vascular disease: venous, arterial, lymphatic, vasculitis, hypertensive

Neuropathic:Peripheral neuropathy, diabetes, alcohol, medication, hereditaryCentral neuropathy: tabes dorsalis, multiple sclerosis, polio, spina bifida, myelodysplasia

Metabolic: Diabetes mellitus, gout, Gaucher disease, amyloidosis, calciphylaxis, porphyria,

Hematologic: Sickle cell, thalassemia, polycythemia vera, lymphoma, protein C and S,

antithrombin, activated protein C resistance, PAI-1, thrombocythemia

Autoimmune: RA, PAN, SLE, Sjogren's syndrome, Wegener granulomatosis, Churg-Strauss

Exogenous: Heat, cold, ionizing radiation, chemical, trauma, allergens

Neoplasia: Basal cell, squamous cell, malignant melanoma, angiosarcoma

Infection: Bacterial, viral, fungal, parasites

Medication: hydroxyurea, methotrexate, coumarin, ergotamine, infiltration

Genetic defect: Klinefelter syndrome, Felty syndrome, inherited hypercoagulable factors

Skin disorder: Pyoderma gangrenosum, sarcoidosis, bullous skin diseases, NLD

Unusual Causes of Leg Ulcers

J Vasc Surg. 2014;60;3S-59S.

Venous Ulcers

• Approximately 80% of all leg ulcers

• Located mainly in the Gaiter area

• Irregular, shallow

• Ulcer base – good granulation tissue

• Skin: crusty, cracked, oozing

• Edema, hyperpigmentation

• Lipodermatosclerosis

Dermatologic Therapy. 2013;26:181-186.

Am Fam Physician. 2010;81(8):989-996.

Arterial Ulcers

• Painful at rest, relieved by dependency

• Find on boney prominences, tips of toes, lateral malleolus, pretibial regions

• Ulcers - sharply demarcated, punched out

• Base pale, gray, yellow, dry or necrotic

• At risk for amputation

Mixed Arterial and Venous Ulcers

International Wound Journal. 2014;11(5):546-549.

J Vasc Surg. 2014;60;3S-59S.

• Underappreciated, unrecognized • 15 - 25% of venous ulcers have an

arterial component (PAD)• Decreased pulses• Painful, fibrotic • Avoid compression if:

- ABI is < 0.5- ankle pressure < 60 mmHg

Hypertensive Ulcers

•Rare, controversial (if exist)

• Found on the lateral ankle

• Ischemic

•Central necrotic ulcer (cyanotic halo)

•Palpable pulses, normal ABI

•HTN (long standing, poor control)

Atlas of Clinical Vascular Medicine, ED. Mintz J, Mintz BL, Jaff MR. 2013 John Wiley & Sons, p116.

Lymphatic Ulcers

Microsurgery 2014;34:64-67

Primary Secondary(More Common)

Congenital (Age<1yr) Chronic venous insufficiency

Lymphedema Praecox (Age 1-35 years)

Filariasis

Lymphedema Tarda (Age > 35 years) Recurrent infection

More common in females Surgery involving lymphatics

Can manifest at birth to early 40s Radiation therapy

Family history Malignancy

Trauma

Wounds often reported to be intractablePatients wound felt due to lymphostasis

Neurotrophic Ulcers

• Found on pressure points: plantar surfaces, medial and lateral metatarsal heads, base of the great toe, posterior heel pad

• Ulcers – may be deep and tracking surrounded by acute/chronic inflammation, and callus formation

• Result from neuropathy, PAD, infection

• Painless

• Failure to heal - due to inadequate offloading

Calciphylaxis

• Painful, mottled, livedoid lesions that evolve into nonhealing, necrotic ulcers, gangrene

• Symmetrical found in adipose areas:

- abdomen, buttocks, thighs, calves

• ESRD (dialysis), primary hyperparathyroidism

• Obese, diabetes, protein S or C deficiency

• Elevated PTH, calcium X phosphorus product > 70 (risk factor)

• High morbidity – death from sepsis

Gout

• History of recurrent attacks of acute and chronic arthritis

• Yellow-white urate deposits that ulcerate

• Biopsies – urate crystals

Japanese Dermatology 2010;37:998-999

Hematologic Ulcers

• Occur in lower extremities

• Very painful

• Local wound care

• Hydroxyurea (increases Hgb F)

• Transfusion(s)

Atlas of Clinical Vascular Medicine, ED. Mintz J, Mintz BL, Jaff MR. 2013 John Wiley & Sons, p124.

• Ulcers are common

• Well demarcated, medial/lateral malleolus

• Chronic pain, slow to heal

Sickle Cell Anemia Thalassemia Intermedia

Hematologic Ulcers - Hereditary Spherocytosis

• Spherical shaped erythrocytes

• Asymptomatic/fulminant hemolytic anemia

• Ulceration - rare

• Altered red cell deformity, increased blood viscosity leads to impaired skin nutrition and ulceration

• Predilection for gaiter area suggests venous stasis plays a role

• Treatment - splenectomy

Southern Medical Journal 2011;104(2): 150-152

Hematologic Ulcers - Cryoglobulinemia

• Plasma proteins precipitate when cooled and dissolve when heated

• Increased blood viscosity

• Acrocyanosis, digital ulcerations on exposure to cold, neuropathy, polyarthralgias

• Blood samples must be collected and transported and clotted at 37° C to prevent false-negatives

• Seen in patients with macroglobulinemia, multiple myeloma, MGUS, hepatitis C, infections

• Plasmapheresis, chemotherapy, steroids

NEJM. 2014;370:1148

JAMA Dermatology. 2015;151(6):659-660

Family history of Waldenstrom’s Macroglobulinemia Patient found to have IgM monoclonal gammopathy of unknown

significance

Type I Cryoglobulinemia with multiple myeloma

Hematologic Ulcers - Cold Agglutinins

• Hemolysis (agglutination), cold-induced circulatory symptoms: Raynaud’s disease, acrocyanosis, cutaneous necrosis

• Diagnosis: hemolytic anemia, reticulocytosis, hyperbilirubinemia, elevated LDH and positive Coombs

• Infections (mycoplasma pneumonia), underlying malignancies (lymphoproliferative disorders, MGUS) and autoimmune disease (SLE, RA), rarely infectious mononucleosis

• Rx: corticosteroids, rituximab

N Engl J Med. 2013;369:e1

Blood. 2013;122(7):1114-1121

Hematologic Ulcers - Cryofibrinogenemia

• Diagnosed when plasma is clear at 37° C but develops a precipitate when cooled to 4 C°

• Symptoms from vascular occlusion occur in cold-exposed areas

• Associated with inflammatory disorders, infection, cancer, renal disorders

• Familial cases described (Autosomal dominant inheritance)

N Engl J Med. 2013;369:8

Nephrol Dial Transplant. 2011;26:3577-3581

Autoimmune/Vasculitis

J Vasc Surg: Venous and Lymphatic Dis 2017;5:280-292

J Rheumatology 2017;43(3):592-598

The International Journal of Lower Extremity Wounds 2016;15(3);263-266

SclerodermaRheumatoid Arthritis

Cutaneous polyarteritis nodosa

Sarcoidosis

Thromboangiitis Obliterans

• Buerger’s disease

• Affects medium-sized arteries, veins and nerves

• Tobacco user

• Tender, ischemic ulcers of the digits and superficial thrombophlebitis

• Tobacco cessation

• Gangrene and amputations

New Engl J Med 2000;343(12):864-869

Infectious Cause of Leg Ulcers

• Patient on long-term immunosuppressive therapy for plasmablastic lymphoma

• Developed acute onset of diverticulits and severe sepsis

• Had a multi-drug resistance Pseudomonas aeruginosa

• Ulcer developed one week after the acute illness

• Biopsy revealed Cytomegalovirus ulcer

• Treated with oral Valganciclovir

JAMA Dermatology 2015;151(6):661-662

Biopsy stained for cytomegalovirus in cytomegalic endothelial cells

Infections Hepatitis C

• Hepatitis C can cause essential mixed cryoglobulinemia (type II) that can result in small to medium vessel vasculitis and ulceration

• B cell directed therapy with rituximab effective treatment

J Vasc Surg: Venous and Lymphatic Dis 2017;5:280-292

Basal Cell Cancer

• Majority of skin cancers

• Sites - exposed to sun

• Most common malignancy of Caucasians

• Low potential for metastasis

• Biopsy recommended for any leg ulcer that does not respond to treatment after several months

8/19/2014

JEADV 2015;29:337-345

Squamous Cell Carcinoma of Calf

• Most prevalent skin cancer of African Americans

• Commonly found - lower extremities

• Can be found in leg ulcers of chronic osteomyelitis, radiation therapy, burn scars and hidradenitis suppurativa

• Marjolin’s ulcer (used to describe malignant tumors occurring in chronic ulcers)

Fitzpatrick's Color Atlas & Synopsis of Clinical Dermatology Klaus Wolff, Richard Allen Johnson, Dick Suurmond

Copyright 2005, 2001, 1997, 1993 by The McGraw-Hill Companies. All Rights reserved.

Malignant Melanoma

• Most commonly affects light-complexion individuals

• Abundant sunshine and exposure to ultraviolet radiation

• Causes 4/5th of all skin cancer deaths

• Ulceration a poor prognosis

Wien Med Wochenschr 2008;158(23):735-738

Hydroxyurea-associated ulcer in patient with polycythemia

Hydroxyurea

• Effective agent for treating select cancers

• Adverse effects include hyperpigmentation, atrophy of the skin and painful leg ulcers in patients with myeloproliferative disorders

• Discontinuation of drug often required

Acta Derm Venereol 2001 373-374

Arch Dermatol 2007;143(10):1310-1313

J Vasc Surg: Venous and Lym Dis 2017;5:280-292

Klinefelter’s Syndrome

•Presence of at least one extra X-chromosome

• Leg ulcers occur in 6% -13% of cases

• Increased risk of varicose veins and venous thromboembolism

JEADV 2003;17:62-64

J Nippon Med Sch 2015;82(1).64-67

Felty’s Syndrome

• Arthritis, leukopenia, splenomegaly

• Felty’s syndrome develops after a long disease course in RA patients

• Ulcers covered by black necrotic tissues associated with peripheral purpura

Acta Derm Venerol 2015;95:754-755

Hypercoagulable States Antiphospholipid Syndrome

•Arterial/venous thrombosis

• Livedo racemosa

• Painful ulceration secondary to ischemia

• Digital gangrene

• Positive lupus anticoagulant, anticardiolipin antibodies, Beta 2 Glycoproteins (IgG, IgM)

Pyoderma Gangrenosum

JAMA. 2014;312(20):2158-2159

• Most common women aged 20 to 50

• Inflammatory bowel disease, inflammatory arthritis, CML, myelodysplasia

• Lesions aggravated by trauma

• Tender pustules or nodules that develop into ulcers with boggy-red to violaceous undermined borders

• Commonly found on leg

• Treat underlying disorder

Erythromelalgia

• Symmetrical most often involves the lower extremities

• Increased skin temperature

• Erythema

•Burning pain

Arch Dermatology. 2000;136:330-336

General Principles of Leg Ulceration Management

• Recognize and treat underlying disease• Arterial disease - revascularization

• Venous disease - compression (control edema)

• Neuropathic disease - off-loading

• Infectious disease - antibiotics

• Wound debridement

• Maintain a moist, clean environment for healing

• Minimize pain

• Recalcitrant ulcers (prolonged duration and/or large size) consider adjunctive methods:• Sclerotherapy

• Endovascular techniques

• Surgery

Davis MDP Leg Ulcerations. In:Rooke TW, editor. Vascular Medicine and Endovascular Interventions. Oxford, UK. 2007 p.141-148.