Are You Confident of the Diagnosis?
Systemic amyloidosis presenting with cutaneous manifestations is most commonly the result of primary systemic amyloidosis (Figure 1). Primary systemic amyloidosis can be subclassified into a type caused by an occult plasma cell dyscrasia, and a myeloma-associated type.
Other systemic forms of amyloidosis, including secondary amyloidosis and hemodialysis-associated amyloidosis, which are both less likely to cause skin findings, as well as the rare heredofamilial syndromes (familial Mediterranean fever, Muckle-Wells syndrome, and familial amyloidotic polyneuropathy), will not be discussed.
Characteristic findings on physical examination
The range of symptoms encountered in primary systemic amyloidosis are mostly related to the degree and type of organ involvement and are often not helpful in suggesting primary systemic amyloidosis as a possible diagnosis. Some of the more common findings during a review of systems include the following: weight loss, weakness/fatigue, dyspnea, edema, paresthesias, light-headedness, syncope, constipation/diarrhea, and hoarseness/change of voice.
Mucocutaneous findings – Approximately 30-40% of patients with primary systemic amyloidosis will present with mucocutaneous lesions. One of the most classic skin lesions is purpura, which can occur after minor trauma (pinch purpura). Periorbital purpura (raccoon eyes) can be elicited by increased intrathoracic pressure as a result of the Valsalva maneuver and coughing. Amyloid infiltration of blood vessels also manifests as petechiae and ecchymoses.
Another characteristic finding in primary systemic amyloidosis is the presence of nontender, nonpruritic papules which can be waxy, translucent or hemorrhagic. A full examination is required because these lesions can occur behind the ears, on the neck, and in the axillae, as well as in the umbilical, inguinal, and anogenital regions. Patients can also less commonly present with nodules and plaques.
Macrogloissia occurs in 20% of patients and is highly suggestive of primary systemic amyloidosis. The tongue will have an increased size and firmness with dental indentations on the lateral borders. Rare cutaneous findings, such as pigmentary changes, scleroderma-like infiltration, bullous lesions, alopecia, cordlike blood vessel thickening, cutis laxa and nail dystrophy, can occur with the above-mentioned, more frequent skin lesions or as the sole cutaneous manifestation of primary systemic amyloidosis.
Other physical fingings – Primary systemic amyloidosis can involve any organ except for the central nervous system; it most commonly affects the kidneys, heart, liver, and peripheral nerves. Findings that can help suggest the diagnosis of primary systemic amyloidosis include signs of nephrotic syndrome, congestive heart failure, carpal tunnel syndrome, and/or autonomic neuropathy such as orthostatic hypotension. Hepatomegaly is usually the most consistent finding during the physical examination.
Expected results of diagnostic studies
Histopathology – For patients with primary systemic amyloidosis, a skin biopsy stained with hematoxylin and eosin will typically show amyloid infiltration as amorphous, eosinophilic masses in the dermis and subcutis without an inflammatory infiltrate. These amyloid deposits are also found surrounding sweat glands, blood vessels and individual fats cells (amyloid rings).
All forms of amyloidosis will demonstrate congophilia with apple-green birefringence under polarized light. Electromicroscopy will also show linear, nonbranching fibrils that are 7.5 to 10 mm wide with indefinite length. In order to confirm the diagnosis of primary systemic amyloidosis, immunohistochemical stains (or other techniques such as amino acid sequencing ) must be positive for lambda or kappa light chains.
Laboratory test – There are currently no specific markers for detecting amyloidosis in biological fluids. There are also no genetic tests associated with the diagnosis of primary systemic amyloidosis. One common finding during routine laboratory testing is proteinuria which is a direct result of the high frequency of kidney involvement in primary systemic amyloidosis.
A patient with nephrotic syndrome, without a clear etiology, should be further evaluated for primary systemic amyloidosis. Once the diagnosis is considered, more definitive tests, such as serum/urine protein electrophoresis, serum/urine immunofixation electrophoresis, and serum/urine free light chain assay, can help establish the presence of an underlying plasma cell dyscrasia.
Other tests – For patients with physical findings suggestive of cardiac involvement, it is important to obtain records for the most recent electrocardiogram and/or echocardiogram, if available. A helpful diagnostic finding in a 12-lead electrocardiogram is low voltage (less than 5 mm) in all limb limbs. In an echocardiogram, the presence of right and left ventricular wall thickening, without a clear etiology such as hypertension, can provide evidence of a restrictive cardiomyopathy due to amyloid deposits.
The cutaneous manifestations of primary systemic amyloidosis mimic many other dermatoses, which often results in a considerable delay in reaching the correct diagnosis. In order to confirm the diagnosis, the skin biopsy must stain positive for Congo red. The presence of immunoglobulin light chains must also be established by immunohistochemical staining or amino acid sequencing. If the results are negative, a biopsy of another affected organ, such as the kidney, should be attempted. Alternatively, an abdominal fat aspirate and bone marrow biopsy are more convenient and, together, provide a relative high yield for positive results in patients with primary systemic amyloidosis.
Another important diagnostic criteria is the existence of a plasma cell dyscrasia. The combination of the serum free light chain assay with serum and urine immunofixation electrophoresis provides a 99% sensitivity for detecting the presence of a plasma cell proliferative disorder. If free light chains are not detected in the serum or urine, then the patient likely has a monoclonal gammopathy of undetermined significance which has a prevalence of 3% in the adult population.
For patients with secondary amyloidosis and certain types of familial amyloidosis, the tissue biopsy will stain positive for serum amyloid A or transthyretin and negative for the presence of kappa and lambda light chains. Localized cutaneous nodular amyloidosis is another important diagnosis to consider because the skin biopsy will stain positive for light chains but internal organ involvement will be absent. For patients diagnosed with nodular amyloidosis, long-term follow-up is necessary for a certain percentage will progress to develop primary systemic amyloidosis.
Other forms of localized cutaneous amyloidosis, such as the more common lichenoid and macular variants, will stain positive for antikeratin antibodies and negative for kappa and lambda light chains. Colloid milium, a localized cutaneous dermatosis due to long-term sun exposure, can mimic localized cutaneous amyloidosis with its ability to stain with Congo red but it also stains negative for light chains.
Who is at risk for Developing Systemic Amyloidosis with Cutaneous Manifestations?
Due the lack of population-based studies, the epidemiology of primary systemic amyloidosis has not been well defined. A frequently cited estimate is the age-adjusted incidence of 5.1 to 12.8 per million persons per year. In one of the largest studies by a tertiary care center, which characterized patients with primary systemic amyloidosis, the mean age at diagnosis was 64 years with 99% of patients being 40 years or older.
There has been no clear environmental, racial, or genetic association linked to primary systemic amyloidosis. The establishment of an international registry could help better determine epidemiologic data and risk factors for this rare disorder.
What is the Cause of Systemic Amyloidosis with Cutaneous Manifestations?
Amyloidosis encompasses many different diseases entities that all share the pathogenic endpoint of organ dysfunction due to the extracellular deposition of fibrils that have an antiparallel beta-pleated sheet configuration. The precursor proteins in primary systemic amyloidosis are monoclonal immunoglobulin light chains resulting from a plasma cell dyscrasia in the bone marrow. The number and type of organs affected by primary systemic amyloidosis varies and it is unknown what determines the site of amyloid deposits.
The exact mechanism that promotes the conversion of immunoglobulin light chains into fibrils is also not entirely clear. Protein sequencing studies have shown that specific amino acids repeatedly occur at certain positions in the variable regions of amyloidogenic light chains. Another factor that could promote an easy transformation into amyloid material involves the high degree of beta-sheets in the normal conformation of immunoglobulin light chains.
Systemic Implications and Complications
Approximately 10% of patients with primary systemic amyloidosis also have multiple myeloma due to a more severe underlying plasma cell dyscrasia. Patients with primary systemic amyloidosis should be evaluated by a hematologist for the presence of multiple myeloma. Screening for multiple myeloma can be initiated with the following tests: complete blood count, peripheral blood smear, basic metabolic panel, B2-microglobulin, lactate dehydrogenase, urine protein electrophoresis and immunofixation, serum protein electrophoresis and immunofixation, and serum free light chain assay.
In all cases, a diagnosis of multiple myeloma requires a bone marrow biopsy. Evidence of end-organ damage, such as hypercalcemia, renal failure, anemia, and bone lesions, will not be present in asymptomatic multiple myeloma. Further details about staging, risk stratification, and treatment of multiple myeloma are best managed by a hematologist and are beyond the scope of this text.
Medical/surgical options for the cutaneous lesions of primary systemic amyloidosiss
Corticosteroids (topical, intralesional)
Electrodesiccation and curettage
Laser therapy (carbon dioxide, pulse dye]]
Chemotherapy options for primary systemic amyloidosis
Melphalan followed by autologous stem cell transplantation (ASCT)
Melphalan and dexamethasone
Thalidomide and dexamethasone (with or without cyclophosphamide), lenalidomide and dexamethasone, only dexamethasone, or bortezomib (with or without dexamethasone)
Optimal Therapeutic Approach for Systemic Amyloidosis with Cutaneous Manifestations
The main aim of treatment for the cutaneous lesions of primary systemic amyloidosis is to improve appearance and function. Several methods for treating nodular cutaneous amyloidosis have been used and include topical and intralesional corticosteroids, cryotherapy, dermabrasion, electrodesiccation with curettage, excision, carbon dioxide laser, and pulsed dye laser.
Despite these therapeutic options, patients should be aware that the cutaneous manifestations of primary systemic amyloidosis are difficult to treat and that more studies are needed to formulate the best treatment options. Dermabrasion and laser therapy have shown promising results but there is not sufficient evidence in the literature to recommend them as first-line therapies.
Before initiating chemotherapy for primary systemic amyloidosis, it is especially important to verify the diagnosis, because other types of systemic amyloidoses are treated much differently. Due to the evolving nature of therapeutic options, patients should be referred to a hematologist at a tertiary care center with expertise in treating primary systemic amyloidosis.Therapy is considered a balancing act between efficacy of the chosen treatment and the patient’s ability to tolerate its side effects.
The main goal of chemotherapy is to at least reduce, if not eliminate, the source of the amyloidogenic light chains. Patients should also receive medical care from other specialists as determined by the type and degree of organs affected by amyloid deposits. These supportive measures are important in decreasing overall morbidity and mortality.
Among the available hematologic treatment options, melphalan followed by autologous stem cell transplantation (ASCT) has the best results for response rates and increased survival for select patients. Thus, many referral centers initiate treatment with melphalan followed by ASCT for patients who meet criteria for ability to tolerate the toxic side effects. For patients deemed ineligible for ASCT, melphalan coupled with dexamethasone is considered the next best treatment option with data showing significant response rates and relative low toxicity compared to other options.
Additional treatments, including thalidomide and dexamethasone (with or without cyclophosphamide), lenalidomide and dexamethasone, only dexamethasone, or bortezomib (with or without dexamethasone), have shown promising results and should be considered in patients who do not appropriately respond to either melphalan followed by ASCT or melphalan coupled with dexamethasone. There are few data available from randomized control trials which directly compares the above-mentioned treatment options. Therefore, whenever possible, patients should be treated in the monitored setting of a clinical trial.
The results from the serum free light chain assay correlate well with long-term response for organs affected by amyloid deposits. A 50% reduction from baseline results of the serum free light chain assay is considered a partial response, whereas a return to normal levels defines a complete response.
In the largest study for patients who received melphalan followed by ASCT, 40% of patients achieved a complete response at the one year mark and 90% of patients achieved a partial response at the one year mark. In a well referenced study for patients who received melphalan coupled with dexamethasone, 33% of patients achieved a complete response and 67% achieved a partial response with a median time of 4.5 months.
Once treatment has been initiated, the management of patients with cutaneous findings of primary systemic amyloidosis can be quite variable among experienced clinicians. Maintenance therapy for the different treatment options has not been clearly defined.
After initiating systemic chemotherapy, close follow-up is necessary in order to monitor the toxic side effects and to monitor serum free light chain levels for treatment efficacy. Patients who are not responding to treatment or having progression of disease within a particular time frame can then be considered for alternative chemotherapy.
It is important for the patient and their family members to know that the mortality rate without systemic treatment is very high for primary systemic amyloidosis. They should also be well informed about ongoing clinical trials involving first-line and alternative therapies.
Unusual Clinical Scenarios to Consider in Patient Management
A major risk of bleeding can be present in patients with primary systemic amyloidosis. Minor hemorrhage can be attributed to the fragility of blood vessels due to amyloid deposits. More severe episodes of bleeding have resulted from acquired coagulation-factor deficiencies, such as Factor X deficiency, as well as acquired Von Willebrand disease. Awareness of the potential bleeding risk in patients with primary systemic amyloidosis is important before obtaining a tissue biopsy.
What is the Evidence?
Breathnach, S. “Amyloid and amyloidosis”. J Am Acad Dermatol. vol. 18. 1988. pp. 1-16. (This 1988 review still offers an excellent overview of primary systemic amyloidosis. Although the prognosis and treatment information is outdated, the sections covering the pathogenesis, histopathology clinical/diagnostic features (including cutaneous findings with images) comprehensively summarizes the current information found in the literature for primary systemic amyloidosis. This manuscript also provides a decent overview of primary localized cutaneous amyloidosis but most of the text is dedicated to primary systemic amyloidosis.)
Borowicz, J, Gillespie, M, Miller, R. “Cutaneous amyloidosis”. Skinmed. vol. 2. 2011. pp. 96-100. (Within this brief overview of cutaneous amyloidosis, this manuscript provides a current summary of the treatment options for nodular cutaneous amyloidosis with a focus on literature findings for dermabrasion, carbon dioxide laser therapy, and pulse dye laser treatment.)
Desai, A, Pielop, J, Smith-Zagone, M, Hsu, S. “Colloid milium: a histopathologic mimicker of nodular amyloidosis”. Arch Dermatol. vol. 142. 2006. pp. 784-5. (This case report provides a brief summary of the similarities between colloid milium and nodular cutaneous amyloidosis and also highlights the important features for distinguishing between these two skin disorders.)
Falk, R, Comenzo, R, Skinner, M. “The systemic amyloidoses”. N Engl J Med. vol. 337. 1997. pp. 898-909. (This well-written review provides comprehensive information on the different types of systemic amyloidoses with a majority of the text covering primary systemic amyloidosis. Topics covered include classification/epidemiology, pathogenesis, clinical features (with classic images), diagnosis, prognosis and treatment. The sections covering prognosis and treatment provided more historical information when compared to more current reviews covering these topics.)
Gertz, M, Merlini, G, Treon, S. “Amyloidosis and Waldenstrom's macroglobulinemia”. Hematology Am Soc Hematol Educ Program. 2004. pp. 257-82. (This well-written manuscript from the hematologist's point-of-view provides an in-depth discussion about primary systemic amyloidosis from suspecting the diagnosis to details about past and current treatments. There is little information concerning the cutaneous manifestations of primary systemic amyloidosis.)
Kyle, R, Gertz, M. “Primary systemic amyloidosis: clinical and laboratory features in 474 cases”. Semin Hematol. vol. 32. 1995. pp. 45-59. (One of the few population-based studies on primary systemic amyloidosis which has provided data for the most common clinical and laboratory features of this disease. This manuscript is frequently cited for the age-adjusted incidence of primary systemic amyloidosis. The study is limited by its recruitment of patients from the surrounding areas of one tertiary care center.)
Kyle, R, Rajkumar, S. “Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma”. Leukemia. vol. 23. 2009. pp. 3-9. (A review by experts in the field covering the diagnostic criteria for multiple myeloma. The information on staging, risk stratification and response assessment of multiple myeloma are more relevant for an audience of hematologists.)
Simms, R, Prout, M, Cohen, A. “The epidemiology of AL and AA amyloidosis”. Baillieres Clin Rheumatol. vol. 8. 1994. pp. 627-34. (This manuscript addresses the need for more population-based studies of primary systemic amyloidosis to derive more accurate epidemiological data concerning age and ethnicity.)
Touart, D, Sau, P. “Cutaneous deposit diseases. Part I”. J Am Acad Dermatol. vol. 39. 1998. pp. 149-71. (This manuscript provides a good overview for the classification as well as the clinical findings and diagnostic criteria for the different types of amyloidosis involving cutaneous manifestations.)
Wechalekar, A, Hawkins, P, Gillmore, J. “Perspectives in treatment of AL amyloidosis”. Br J Haematol. vol. 140. 2008. pp. 365-77. (This review provides an important overview and critical discussion of the data supporting current chemotherapy options for primary systemic amyloidosis.)
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