Response of hemorrhagic bullous skin lesions of the breast secondary to primary systemic amyloidosis to a five-drug combination chemotherapy: a case report and review of the literature
© Agheli et al.; licensee BioMed Central Ltd. 2012
Received: 4 May 2012
Accepted: 30 May 2012
Published: 13 August 2012
Two major types of amyloidosis are primary amyloidosis or amyloid light chain amyloidosis and secondary amyloidosis. Although amyloidosis involves a variety of organ systems including skin, the occurrence of bullous skin lesions is rare. Little is known about the mechanism of blister formation. These blisters are often hemorrhagic and typically occur in the oral mucosa. Only a few case reports have described skin involvement in systemic amyloidosis. The manifestation of bullous lesions on the breast in association with primary amyloidosis has not been previously reported. Therefore, we report a case of cutaneous hemorrhagic bullous of the breast secondary to primary systemic amyloidosis, which may be important for medical oncologists to be aware of this uncommon presentation of plasma cell dysrasias. Furthermore, this case only partially responded to the commonly used multiple myeloma-type regimen, the skin lesions responded completely to a five-drug combination chemotherapy regimen, utilizing immunomodulators, liposomal doxorubicin, cyclophosphamide, bortezomib, and dexamethasone, suggesting that a more aggressive modality of chemotherapy may be necessary to treat such cases.
Primary and secondary amyloidosis are the two major types of amyloidosis. The primary systemic amyloidosis, also known as light chain (AL) amyloidosis, is mostly related to a plasma cell dyscrasia. The secondary (AA) amyloidosis is derived from serum amyloid A subunit protein, an acute-phase protein that is produced in response to inflammatory conditions . There is no identifiable, underlying cause of AL amyloidosis . The fibrils of AL amyloidosis are composed of polymerized immunoglobulin light chain or light chain fragments . Amyloid protein is resistant to proteolysis and has a three dimensional configuration as a beta pleated sheet . Although cutaneous involvement in primary systemic amyloidosis is relatively common , the occurrence of bullous skin lesions is rare [2, 3].
Only a few cases of cutaneous involvement with systemic light chain amyloidosis have been reported in the literature. Skin involvement in the form of hemorrhagic bullous is much rarer. To the best of our knowledge, hemorrhagic bullous presentation of amyloidosis on the breast skin has not been reported in the literature. This uncommon presentation of amyloidosis was only partially responsive to the commonly used combination chemotherapy regimens, but it responded completely to a five-drug combination regimen. This suggests that a more aggressive approach, with combination of multiple immunomodulators and chemotherapy agents may be required to achieve a meaningful response in similar cases.
Bullous pemphigoid (and linear IgA disease) is a heterogeneous group of autoimmune blistering disorders of the subepiderm and is associated with autoantibodies, predominantly IgG, against the transmembrane hemidesmosomal protein BP180/type XVII collagen . Mucous membrane pemphigoid is characterized by subepithelial separation and deposition of immunoglobulins and complement along the basement membrane zone. This disease is diagnosed with direct immunofluorescence testing showing a linear deposition of immunoglobulins and/or complement along the basement membrane zone and indirect immunofluorescence testing showing circulating IgG (and sometimes IgA) autoantibodies along the basement membrane zone .
Light chain (AL) amyloidosis is a plasma cell dyscrasia characterized by the pathologic production and deposition of monoclonal light chain fibrillar proteins in tissues, resulting in organ dysfunction. The goal of treatment of AL amyloidosis is eradication of the monoclonal plasma cell population and suppression of the pathologic levels of light chains. The use of novel agents, such as thalidomide, lenalidomide and bortezomib alone or in combination with steroids and alkylating agents has shown efficacy and continues to be explored . HevyLite™ is a new, recently developed method that facilitates separate quantification of the kappa and lambda-bounded amounts of a given immunoglobulin. This new assay provides precise quantification of heavy and light chain and their ratio of the involved immunoglobulin more accurately than the other currently available methods; moreover, they carry prognostic information regarding survival in multiple myeloma patients .
Primary systemic amyloidosis, a disease characterized by infiltration of different organs , and associated amyloidosis cause clinically detectable cutaneous changes in approximately 10-40% of patients ; The occurrence of bullous skin lesions, however, is rare [2, 3]. The bullae may be intradermal or subepidermal . The bullae form of cutaneous amyloidosis results from cleavage of the amyloid deposits. These blisters are often hemorrhagic and most commonly occur in the oral mucosa .
In this reported case, skin lesions did not reveal immunoglobulin deposits, and indirect immunofluorescence staining for basement membrane protein was negative. Skin biopsy showed positive congo red staining, and amyloid deposits were identified with a positive apple-green birefringence under polarized light microscopy. These findings, along with bone marrow infiltration by abundant plasma cells, multiple lytic bone lesions, and the presence of light chain protein, confirmed a diagnosis of bullous skin lesion secondary to primary systemic amyloidosis.
Summary of the therapeutic regimens used for the treatment of dermatologic manifestations of systemic AL amyloidosis, by the date of publication
1. Beachman et al 
Diffuse Bullous Amyloidosis of skin
(Am Acad Dermatol)
Melphalan + Prednisone
No Clinical CR, 9 mo
2. Ruzicka et al 
(Brit J Dermatol)
3. Bieber et al 
Hemorrhagic Bullous Amyloidosis
Multiple skin folds
Melphalane + Prednisone
Lesions healed with milia
4. Johnson et al 
Non-Hemorrhagic Bullous Amyloidosis
Trunk & Proximal Extremities
Prednisone + Azathioprine
5. Pramatarov et al 
Multiple Hemorrhagic skin Lesions with systemic Amyloidosis
Multiple skin lesions
(Intern J Dermatol)
Cochicine + DMSO
6. Robert et al 
Bullous Amyloidosis of skin, 3 cases
7. Grundmann et al 
Extensive Hemorrhagic Bollous AA-Amyloidosis
(Eur J. Med)
Dexamethasone Stabilized after 3 cycles
8. Ochiai et al 
Bullous Pemphigoid Amyloidosis of Hands Systemic AA-amyloidosis
Hands & Feet
(J Cutan Pathol)
9. Comenzo et al 
Review Article Systemic Amyloidosis
Melphalane + ASCT
100-day mortality of 21-39 %
10. Gertz et al 
Primary Systemic Amyloidosis
(Am J Medicine)
Treatment-related Mortality of 14 %
11. Goodman et al 
(Brit J Haem)
HD chemotherapy + 100-day mortality ASCT
12. Giovanni et al 
(52nd ASH Meeting)
Lenalidomide + Dexamethasone Mortality 13 %
No CR, PHR 41 %,
It is important to know that 43% of the patients with amyloidosis, who are treated with lenalidomide, may develop skin rashes. The rashes are characterized as morbilliform, urticarial, dermatitic, acneiform, and undefined. Severe rashes require permanent discontinuation of lenalidomide .
This unique reported case of AL amyloidosis presented with hemorrhagic bullous skin lesions, high levels of light chain protein only, presence of t(11,14) by cytogenic study, overexpression of cyclin D1, and only partial response to the standard multiple myeloma regimen, which includes lenalidomide and bortezomib, and dexamethasone (RVD). All these features represent a poor prognosis [20–22]. A more aggressive treatment approach with combination of five agents resulted in achieving meaningful success. This included combination of lenalidomide, bortezomib, liposomal doxorubicin, cyclophosphamide, and dexamethasone. The overall response included a very good partial response (VGPR), associated with a great than 90% reduction in the kappa light chain level, and complete resolution of the breast skin lesions. This case illustrates that bullous hemorrhagic skin lesions, associated with primary systemic amyloidosis may need more aggressive treatment such as the five-drug combination that we have used.
The patient of the interest in this manuscript has been aware of our intention to publish her case. She has consented to publishing the manuscript without including any pertinent information, which may disclose her identity. We have done our best to protect her identity in this paper.
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