Diagnostic Dilemma: Primary Localized Cutaneous Amyloidosis, Macular Type

Department Editor Tania Phillips, MD, FRCPC Overall Learning Objectives: The physician or podiatrist participant will develop a rational approach to the evaluation and treatment of a variety of uncommon wounds and will have an increased awareness of the differential diagnosis of cutaneous wounds and the systemic diseases associated with these wounds. Submissions: To submit a case for consideration in Diagnostic Dilemmas, e-mail or write to: Executive Editor, WOUNDS, 83 General Warren Blvd., Suite 100, Malvern, PA 19355, eklumpp@hmpcommunications.com Completion Time: The estimated time to completion for this activity is 1 hour. Target Audience: This CME/CPME activity is intended for dermatologists, surgeons, podiatrists, internists, and other physicians who treat wounds. At the conclusion of this activity, the participant should be able to: 1. Discuss an interesting presentation of a leg ulcer. 2. Differentiate localized cutaneous amyloidosis from systemic amyloidosis. 3. Briefly discuss the difference between primary and secondary localized cutaneous amyloidosis. 4. Discuss the cutaneous amyloidoses with an emphasis on the more common macular and lichen forms. 5. Discuss management of this case of macular amyloidosis and leg ulcer. Disclosure: All faculty participating in Continuing Medical Education programs sponsored by HMP Communications are expected to disclose to the program audience any real or apparent conflict(s) of interest related to the content of their presentation. Drs. Lin and Phillips disclose no financial conflicts. Accreditation: HMP Communications is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications is approved by the Council on Podiatric Medical Education as a sponsor of continuing education in podiatric medicine. Designation: HMP Communications designates this continuing medical education activity for 1 credit hour in Category 1 of the Physician’s Recognition Award of the American Medical Association. Each physician should claim only those hours he/she spent in the educational activity. HMP Communications designates this continuing education activity for .1 CEUs available to participating podiatrists. Method of Participation: Read the article, take, submit, and pass post-test by September 15, 2003. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies. Release date: September 15, 2002 Expiration date: September 15, 2003 Presentation A 62-year-old Hispanic woman presented with a history of intermittent ulcers on both lower extremities for two years prior to presentation. She complained of diffuse pruritus of her entire body, including itching in her legs, of which she admitted that she often scratched, causing small blisters filled with clear fluid. The pruritic blisters often progressed to painful ulceration, which had a history of slow healing and a minimal amount of drainage. Two-percent mupirocin ointment seemed to help heal her ulcers. Her past medical history was significant for diabetes (20 years) for which she was taking oral hypoglycemic agents (glyburide and metformin). She had no history of deep venous thrombosis, cellulitis, surgery, or trauma to the legs. She denied arthritis, tobacco and alcohol use, hypertension, and cerebral or cardiovascular disease. Her past surgical history included appendectomy and hysterectomy. In addition to her oral hypoglycemic agents and occasional 2% Mupirocin ointment use, she was taking simvastatin. Her family history was negative for leg ulcers. Physical Examination Physical examination revealed a petite Hispanic woman with diffusely xerotic skin. Cutaneous exam also revealed macular hyperpigmentation in a rippled pattern over her forearms, shoulders, back, buttocks, and upper thighs (Figure 1). She had small hypopigmented scars on her forearms and excoriations over her shoulders and buttocks as well as numerous circular hypopigmented scars over her shins and calves. One superficial, noninfected-appearing ulcer measuring 4cm x 2cm was present on the right medial calf (Figures 2 and 3). She also had a 1cm x 1cm healing ulcer on the left medial calf and showed no evidence of jaundice, lymphadenopathy, or hepatosplenomegaly. Her ankle brachial pressure index was 0.8 bilaterally. Investigations A 3mm punch biopsy was performed on the patient’s upper back. Histology revealed increased basal keratinocytic pigmentation, focal deposition of globular amphorphilic material in the papillary dermis, and melanophages consistent with macular amyloidosis (Figures 4 and 5). Bloodwork revealed a mildly elevated blood urea nitrogen (BUN) of 26 (normal 6–22mg/dL) with a normal creatinine. Random glucose was elevated at 349 (normal 70–115mg/dL), and her hemoglobin A1C was 12.1 (normal 4–6%). She had a high ESR of 90 (normal 0–30mm/hr), and her alkaline phosphatase was elevated at 144 (normal 35–120 U/L). X-ray of the patient’s left knee showed only minimal degenerative changes. Diagnosis This patient had macular amyloidosis, confirmed by histologic demonstration of amyloid material in the tissue biopsy specimen, which contributed to the pruritus on her legs. The leg ulcers were likely artifactual in nature, secondary to scratching of her legs. The history of blisters may have been related to her diabetes and/or infection. Discussion Amyloidosis. Amyloidosis is a term representing a group of related diseases having in common the presence of extracellular amyloid deposition.1 Amyloid is composed of aggregated fibril proteins that are 7.5nm to 10nm in diameter, hollow, and contain two or more rigid filamentous units.1,2 The exact composition of the amyloid fibrils differs depending on the specific class of amyloid disease (Table 1).1 Systemic amyloidosis. Systemic amyloidosis may be classified into primary and secondary types. Primary systemic amyloidosis is associated with multiple myeloma; whereas, secondary is associated with other chronic diseases, including chronic infection, rheumatoid arthritis, inflammatory bowel disease, Hodgkin’s disease, and some solid nonlymphoid tumors.2 Secondary systemic amyloidosis is associated with conditions including epidermolysis bullosa (dystrophic and acquisita types), recurrent venous ulceration, generalized psoriasis, psoriatic arthritis, lepromatous leprosy, and ulcerated basal cell carcinoma.2 In primary systemic amyloidosis, amyloid deposition typically occurs in the tongue, heart, gastrointestinal tract, skeletal systems, smooth muscles, carpal ligaments, nerves, and skin.2 Cutaneous involvement in primary systemic amyloidosis may present as waxy, purpuric papules on the eyelids.2,3 In secondary systemic amyloidosis, the liver, spleen, kidneys, and adrenal glands are mainly affected.2 Cutaneous lesions secondary to amyloid deposition are not usually a feature of secondary systemic amyloidosis.2–4 The composition of the amyloid fibril depends on the particular type of amyloidosis.2 In primary systemic amyloidosis, fibrils are composed of immunoglobulin light chains.2 In secondary systemic amyloidosis, the amyloid fibrils are composed of a non-immunoglobulin protein, termed serum amyloid-A protein, which is an acute phase reactant produced by the liver.2,5 Cutaneous amyloidosis. Amyloid deposition disease may occur independently of systemic disease, in which case it is termed localized cutaneous amyloidosis.5 Localized cutaneous amyloidosis may also be classified into primary and secondary types. In primary cutaneous amyloidosis, amyloid deposition occurs in the papillary dermis1 of the skin without evidence of deposition in internal organs.6 The precursor protein of the amyloid deposits is believed to be keratin.1 Several distinct clinical forms of primary cutaneous amyloidosis exist, but the most common are the macular and papular forms (lichen amyloidosis).5,6 The lichenoid is more common than the macular form.7,8 The nodular (tumefactive) form of cutaneous amyloidosis is exceedingly rare.3 Clinical presentation and histopathologic findings are dramatic.3 Nodular localized cutaneous amyloidosis may present with a single lesion or multiple lesions ranging in size from a few millimeters to several centimeters, anywhere on the body, closely resembling lesions associated with plasma cell dyscrasia-related systemic amyloidosis.2 Interestingly, correct clinical diagnosis of the nodular type before biopsy has never been made.3 Secondary localized cutaneous amyloidosis may be secondary to other phenomenon including intradermal nevi, sweat gland tumors, pilomatricoma, dermatofibroma, seborrheic keratosis, actinic keratosis, porokeratosis of Mibelli, Bowen’s disease, and basal cell carcinoma.4 These amyloid deposits do not have a known clinical significance.3 There is no known documented case of progression of lichen amyloidosis or macular amyloidosis to systemic disease.2,5 Interestingly, although nodular localized cutaneous amyloidosis often follows a chronic benign course, paraproteinemia and overt systemic amyloidosis have been reported.2,5 Primary localized macular and lichen amyloidosis. Macular and papular (lichen amyloidosis) variants of primary cutaneous amyloidosis may have a familial and/or racial basis.2,6 Macular amyloidosis is more frequent in Central and South Americans, Middle Easterners, and Asians.2,4,6 Lichen amyloidosis is more common in Chinese. One study found that the age of onset of affected patients was 30 years old (range 21 to 60 years) and a median duration of disease of three years (range 3 months to 26 years).3 None of the patients in that study had a history of atopic disease or a family history of any form of amyloidosis.3 Clinical Features History. Macular amyloidosis is a mildly to moderately pruritic and pigmented eruption, most commonly found on the upper trunk (chest, back, and shoulders) or extremities (pretibial areas).1,3,6 Lichen amyloidosis presents as firm yellow-brown papules, found most commonly on the pre-tibial areas that may group to form small plaques.3,5 Lesions are usually very pruritic and become lichenified after persistent scratching.5 Features of macular and lichen amyloidosis may coexist.7 Physical examination. In macular amyloidosis, the predominant lesion is usually a 2mm to 3mm hyperpigmented (dusky brown to grayish) macule.2,6 The macules are often distributed symmetrically, most commonly on the trunk,9 affecting the chest, upper back, and shoulders but may also involve buttocks and limbs.2,3,6 Areas of confluent macular pigmentation may be found.6 A reticulated or “rippled” pattern of hyperpigmentation is sometimes observed.3,6 Deeply pigmented micropapules may be seen within long-standing areas of confluent macular lesions.6 These micropapules are usually not as large as those in classical papular form of lichen amyloidosis.6 Lesions have a prolonged course and often persist unchanged for several years.2 Extensive involvement has been reported but is rare.7–9 Lichen amyloidosis presents as multiple, discrete, pruritic, hyperkeratotic papules, most commonly presenting on the shins.2 Papules may coalesce to plaques and may affect calves, ankles, dorsal feet, and thighs.2 Extensor arms, chest, and abdominal surfaces may also be affected.2 Unusual variants of the macular type 2 have been reported including periocular hyperpigmentation, a poikiloderma-like form, nevoid hyperpigmentation, and anosacral cutaneous amyloidosis.2 Isolated reported associations between primary localized cutaneous amyloidosis has occurred with connective tissue diseases, including systemic lupus erythematosus, systemic sclerosis, and primary biliary cirrhosis, as well as celiac disease with eczema.2 Pathogenesis. Deposition of amyloid in the skin without evidence of deposition in internal organs occurs in primary cutaneous amyloidosis.6 The etiology of the amyloid fibril protein in lichen amyloidosis and macular amyloidosis is currently an enigma2,10 but is thought to be derived from damaged keratin filaments that originate from keratinocytes that have undergone apoptosis and have deposited in the papillary dermis.5 The amyloid in primary localized cutaneous amyloidosis is postulated to be derived from keratin, since cross reactivity of some product in the amyloid deposit occurs with keratin.2,10 This product has also been shown to contain disulfide bonds, as does keratin.2 It has been suggested that degenerating epidermal cells may be converted into, or in some manner provide the substrate for, the formation of amyloid in the dermo-epidermal junction region.6,11 The keratinocytes are thought to undergo filamentous degeneration and apoptosis.2 The filamentous aggregates are thought to be converted into amyloid material in the papillary dermis2,10 by macrophages or fibroblasts,2 as some have noted dermal fibroblasts in proximity to amyloid deposits containing amyloid-like filaments.2 It has also been hypothesized that perhaps basal cells at the epidermo-dermal junction produce the amyloid.11 Pigmentary incontinence and the disturbance of melanocytes above the amyloid deposits may occur3 and are suggestive of basal epidermal layer damage. Thus, it may be postulated that amyloid formation may not be a primary process but rather secondary to a disease process affecting the lower epidermis.6 Histopathology. On hematoxylin-eosin staining, eosinophilic masses are visualized in the papillae with rete ridge thinning, elongation, or obliteration.1,2,6 Congo red, the most specific stain for amyloidosis, reveals a green bifringence under polarized light.1 Blood vessels, nerves, subcutaneous tissue, and adnexal structures are usually spared.2,7 Lichen amyloidosis and macular amyloidosis deposits are similar, and in fact, both macular and lichen amyloidosis may coexist in one individual.2,10 It has been postulated that the diseases may be opposing extremes of the same pathological process,1,2,10 with one end being the lichenoid form and the other being the nearly imperceptible macular form.1 Minor differences histologically include that in macular amyloidosis, the overlying epidermis sometimes showed acanthosis and broadening and elongation of the rete ridges.2,6 The deposits of macular amyloidosis are also slightly larger than in lichen amyloidosis.2 The histopathology of nodular primary localized cutaneous amyloidosis is similar to that of macular and lichen forms, with the exception that there is usually a marked infiltration of plasma cells.2 Treatment. Available treatment modalities have been disappointing.10 Deposits may be surgically excised or treated with the carbon dioxide laser, although local recurrence is a concern.2 The course is usually chronic with intractable pruritus despite topical steroids and oral antihistamines.2 Lichen amyloidosis may benefit from dermabrasion according to anecdotal reports.2 Topical dimethylsulfoxide has been reported to help in one case of lichen amyloidosis but not macular amyloidosis.2,10 Etretinate therapy has shown variable results ranging from being ineffective to completely clearing lesions.2 Patient Examination This patient was advised to keep her fingernails short and to avoid scratching her skin. The authors recommended the use of mild soaps and liberal use of lubricants. Triamcinolone acetonide ointment 0.1% was recommended to particularly pruritic areas. For the ulcer, 2% mupirocin with a hydrocolloid dressing was used. The ulcer healed by the follow-up visit two weeks later (Figure 6). Questions 1. In primary systemic amyloidosis, skin lesions typically occur on the: A. Upper back B. Pretibial area C. Tongue D. Eyelids E. No skin lesion 2. In secondary systemic amyloidosis, skin lesions typically occur on the: A. Upper back B. Pretibial area C. Tongue D. Eyelids E. No skin lesion 3. Lichenoid cutaneous amyloid lesions typically occur on the: A. Upper back B. Pretibial area C. Tongue D. Eyelids E. No skin lesion 4. Macular cutaneous amyloid lesions typically occur on the: A. Upper back B. Pretibial area C. Tongue D. Eyelids E. No skin lesion 5. In primary systemic amyloidosis, the fibrils are composed of: A. Immunoglobulin light chains B. Epidermal cells through filamentous degeneration C. Serum amyloid-A protein D. All of the above E. None of the above 6. In primary (lichenoid or macular) localized cutaneous amyloidosis, the fibrils are composed of: A. Immunoglobulin light chains B. Epidermal cells through filamentous degeneration C. Serum amyloid-A protein D. All of the above E. None of the above 7. In primary (nodular) localized cutaneous amyloidosis, the fibrils are composed of: A. Immunoglobulin light chains B. Epidermal cells through filamentous degeneration C. Serum amyloid-A protein D. All of the above E. None of the above 8. In secondary systemic amyloidosis, the fibrils are composed of: A. Immunoglobulin light chains B. Epidermal cells through filamentous degeneration C. Serum amyloid-A protein D. All of the above E. None of the above Primary Localized Cutaneous Amyloidosis, Macular Type Answer Form and Evaluation Please print clearly: Name Degree Position/Title Organization/Institute Department Mailing Address for Certificate (H or W): City State Zip Code Email Address Social Security Number Phone (area code) Fax (area code) Answers (Refer to questions above) Circle or click one letter for each answer: 1. A B C D E 2. A B C D E 3. A B C D E 4. A B C D E 5. A B C D E 6. A B C D E 7. A B C D E 8. A B C D E Evaluation (circle or click one) Excellent (4) Good (3) Satisfactory (2) Poor (1) Accuracy and timeliness of content: 4 3 2 1 Relevance to your daily practice: 4 3 2 1 Impact on your professional effectiveness: 4 3 2 1 Relevance of the content to the learning objectives: 4 3 2 1 Effectiveness of the teaching/learning methods: 4 3 2 1 This activity avoided commercial bias or influence YES NO Now that you have read this article, can you: 1. Discuss an interesting presentation of a leg ulcer? YES NO 2. Differentiate localized cutaneous amyloidosis from systemic amyloidosis? YES NO 3. Briefly discuss difference between primary and secondary localized cutaneous amyloidosis? YES NO 4. Discuss the cutaneous amyloidoses with an emphasis on the more common macular and lichen forms? YES NO 5. Discuss management of this case of macular amyloidosis and leg ulcer? YES NO What questions do you still have?________________________________________________________ How will you use what you have learned from this activity?___________________________________________________ All tests must be received by 9/15/03.