Gene rearrangement studies in the diagnosis of primary systemic and nodular primary localized cutaneous amyloidosis

Difficulties may arise in the diagnosis of patients with clinical features suggestive of plasma cell dyscrasia-related amyloidosis (amyloidosis L), but without evidence of a paraprotein. We have employed gene rearrangement methodology to demonstrate the clonality of bone marrow cells not only in a patient with myeloma-associated systemic amyloidosis, but also in a patient with "primary" systemic amyloidosis without overt myeloma or a detectable paraprotein. Furthermore, we have shown the clonality of the amyloid-producing plasma cells within a skin nodule of a patient with primary localized cutaneous amyloidosis; by contrast, clonal rearrangement was not detected in bone marrow cells from this patient. This finding provides definitive proof that organ-limited nodular primary localized cutaneous amyloid deposits arise in relation to cutaneous plasmacytomas. Gene rearrangement studies may enable early diagnosis and initiation of treatment in patients with systemic amyloidosis L, as well as their differentiation from patients with organ-limited nodular cutaneous amyloidosis, who do not require aggressive therapy.     

Bullous poikilodermatitic amyloidosis of the skin with junctional bulla development in IgG light chain plasmacytoma of the lambda type. Histology, immunohistology and electron microscopy]

A 75-year-old patient presented with bullae, poilokilodermatic skin and nail dystrophy as signs of systemic amyloidosis 1 year before an IgG myeloma of the lambda type was diagnosed. The skin lesions appeared at mechanically irritated locations on the trunk and at the tensor sites of the extremities. Histology showed a subepidermal blister and necrotic keratinocytes in the epidermis. There were amyloid deposits in the papillary dermis perivascular, and in the deep dermis around eccrine glands and in arrectores pilorum muscles. Polyclonal antibodies allowed classification of the deposits as amyloid composed of lambda light-chain immunoglobulins. Electron microscopy revealed globoid deposits of non-branching filaments typical of amyloid. The blister was formed at the level of the lamina lucida, with the lamina densa at the base of the bottom of the bulla. So far, junctional blister formation in bullous amyloidosis of the skin has been described only once. Our case is the second report of this blister type, and to our knowledge the first published report of a junctional blister in myeloma-associated systemic amyloidosis.     

Partial amino acid sequence of an amyloid fibril protein from unusual cutaneous cystic lesions in myeloma-associated amyloidosis

Although common cutaneous lesions in myeloma-associated systemic amyloidosis are petechiae, purpura, ecchymoses, plaques, waxy, translucent or purpuric papules or nodules, we encountered an unusual case of myeloma-associated amyloidosis with multiple cystic nodules. We isolated amyloid substance from the cutaneous cystic nodules of this patient and characterized it ultrastructurally, immunologically, and biochemically. Electron microscopy demonstrated that amyloid substances isolated by distilled water were principally straight and non-branching fibrils with a diameter of 8 to 10 nm, which was morphologically similar to amyloid fibrils. SDS-PAGE showed that these fibrils consisted of the 20 kDa and 29 kDa peptides, which reacted with the antibody to kappa light chain of immunoglobulin by immunoblot study. Partial amino acid sequence of N-terminal residues of this 20 kDa peptide showed a homology to kappa immunoglobulin light chain of variable subgroup I. These results suggest that amyloid fibrils in this unusual case with cutaneous cystic nodules may be derived from kappa I light chain of immunoglobulin.     

Primary systemic amyloidosis associated with multiple myeloma

This case report is about a 48-year-old female patient with systemic amyloidosis and multiple myeloma simultaneously. Amyloid cutaneous infiltrative lesions like papules, nodules, or plaques with a serous-hemorrhagic aspect were found in the eyelids, neck and retroauricular region, among others. She had presented intermittent papular lesions on the upper eyelids one year before, which worsened following local trauma. A local skin biopsy showed amorphous and eosinophilic substance in the dermis. Congo red staining confirmed the amyloid deposits. Abnormal exams: proteinuria (570 mg/24h), Bence-Jones proteinuria and clonal plasma cells (70%) found in myelogram. Following the diagnosis of multiple myeloma based on amyloid skin lesions, the patient was referred to the Hematology service and died 5 months after the diagnosis.     

Amyloid in localized cutaneous amyloidosis: immunofluorescence studies with anti-keratin antiserum especially concerning the difference between systemic and localized cutaneous amyloidosis

Amyloid of localized cutaneous amyloidosis and systemic amyloidosis were subjected to study with an indirect immunofluorescence technique using anti-keratin antiserum. Anti-keratin antiserum was prepared ad modum Sun & Green. Amyloid of localized cutaneous amyloidosis was positively stained for the antiserum, whereas amyloid of systemic amyloidosis (primary and multiple myeloma-associated) was negative. There was no difference between primary localized cutaneous amyloidosis (lichen amyloidosus and macular amyloidosis) and secondary localized cutaneous amyloidosis (amyloidosis associated with skin tumor). These results indicate that amyloid of localized cutaneous amyloidosis contains components derived from epidermal fibrous protein, probably tonofilaments of keratinocytes.     

Recurrent chancriform mucous membrane ulcer in plasmacytoma with secondary IgA deficiency. Pyoderma chancriforme of the tongue

A 66 year old patient presented with a nine month history of recurrent oral ulcerations involving the tongue. We diagnosed chancriform pyoderma and a previously not identified multiple myeloma with secondary immunoglobulin deficiency. Clinically and histologically we excluded a necrotizing ulcerative stomatitis as found in individuals with cellular immunodeficiency as in late-stage HIV-infection. On culture only Neisseria catarrhalis was found. Chancriform pyoderma is often associated with local bacterial infections, especially Staphylococcus aureus. The most common sites are the genitalia and periorbital region; involvement of the oral mucosa is uncommon. To the best of our knowledge, this is the fourth reported case with tongue lesions. The multiple myeloma-associated immunoglobulin deficiency might have facilitated the oral manifestations of chancriform pyoderma.     

Nail abnormalities and scleroderma-like lesions on the face associated with systemic amyloidosis

INTRODUCTION: Mucocutaneous involvement in systemic amyloidosis occurs in 29 to 40 p. 100 of cases. Nail abnormalities are infrequent in AL amyloidosis. We report an original case of AL amyloidosis associated with cutaneous and integument alterations and scleroderma-like infiltration of the face. CASE REPORT: A 73 year-old woman was hospitalized because of weight loss and asthenia. She had been treated 4 years earlier with chemotherapy for a IgG-type multiple myeloma with complete resolution of the underlying monoclonal gammapathy. Cutaneous examination showed nail dystrophy of all fingernails associated with scleroderma-like skin changes on the chin and lips. Histopathologic study of a chin biopsy confirmed the presence of amyloid deposits in the dermis. Laboratory data were normal, without signs of recurrence of multiple myeloma. DISCUSSION: We report an original case of a patient who developed two unusual cutaneous manifestations associated with AL amyloidosis. Moreover, there was no correlation between the severity of the cutaneous lesions and the extent of the underlying hematological disease.     

Light chain multiple myeloma with cutaneous AL amyloidosis

Cutaneous AL amyloidosis is one complication of multiple myeloma. In our patient, painful sclerotic skin changes on the extremities and macroglossia were the presenting features which led to a more detailed investigation and the diagnosis of multiple myeloma. Histological examination revealed cutaneous deposits of amyloid which were positive with Congo red stain and had an apple green color in polarized light.     

Dermatologic adverse effects of lenalidomide therapy for amyloidosis and multiple myeloma

OBJECTIVES: To examine dermatologic adverse effects of lenalidomide in patients with amyloidosis and multiple myeloma and to determine whether the adverse effects are different when lenalidomide is used alone compared with when it is used in combination with dexamethasone. DESIGN: Retrospective review of medical records. SETTING: Tertiary referral center. PATIENTS: Seventy-five patients with multiple myeloma and 23 patients with amyloidosis participating in clinical trials. INTERVENTION: In the 75 patients with multiple myeloma, lenalidomide was the treatment in 24 and lenalidomide and dexamethasone in 51. In the 23 patients with amyloidosis, lenalidomide was used alone. MAIN OUTCOME MEASURES: The frequency, type, severity, and time of onset of all skin eruptions that were temporally related to lenalidomide treatment were recorded. RESULTS: In the patients with amyloidosis treated with lenalidomide, 10 (43%) had rashes. In the patients with multiple myeloma, rashes occurred in 7 (29%) of those receiving lenalidomide alone and in 15 (29%) of those receiving lenalidomide and dexamethasone. The rashes were characterized as morbilliform, urticarial, dermatitic, acneiform, and undefined. Severe rashes required permanent discontinuation of lenalidomide therapy in 2 patients. In 23 patients (72%), rashes occurred in the first month after therapy was initiated; however, delayed-onset rashes occurred in 9 (28%). CONCLUSIONS: The prevalence of dermatologic adverse effects in patients receiving lenalidomide was higher in those with amyloidosis than in those with multiple myeloma. The prevalence of skin eruptions was not diminished by the concurrent use of systemic corticosteroids. Most skin eruptions were mild and did not necessitate withdrawal of lenalidomide therapy.     

原发性系统性淀粉样变病1例

报告1例原发性系统性淀粉样变病。患者男，39岁。1年前肩关节突然出现酸痛，症状渐渐加重，双手掌皮肤发硬，肢体上抬及下蹲困难，舌不能外伸，吞咽时有梗阻感。曾经患有胸椎椎体骨髓瘤。皮肤科检查示面颈部、双侧腋下、腹部、阴茎、双大腿内侧泛发对称性的蜡样半球形丘疹，有融合，呈肤色或琥珀色。口腔黏膜肥厚，舌弥漫性浸润、质硬，呈巨舌。皮损组织病理检查示表皮萎缩，真皮与皮下组织淀粉样物质沉积，甲基紫染色阳性，诊断为原发性系统性淀粉样变病。给予泼尼松和雷公藤治疗，症状明显改善。     

Relapsing bullous amyloidosis of the oral mucosa and acquired cutis laxa in a patient with multiple myeloma: a rare triple association

It is well known that primary systemic amyloidosis [light chain (AL) amyloidosis] is associated with hidden dyscrasia or multiple myeloma. Acquired cutis laxa (cutis laxa acquisita; CLA) has also been described in patients with plasma cell dyscrasias, including multiple myeloma. We report a case in which haemorrhagic oral bullae were the first sign of an undiagnosed primary systemic amyloidosis related to multiple myeloma IgG‐λ and previously diagnosed CLA. There is only one report in literature of this rare triple association; however, in that case the patient did not have oral mucosal involvement or bullous amyloidosis.     

Unusual clinical presentation of amyloidosis: bilateral stenosis of the external auditory canal, hoarseness and a rapid course of cutaneous lesions

We report a patient with multiple myeloma associated with primary systemic amyloidosis who had a rapid evolution and a very unusual form of presentation. The association of amyloidosis in patients with multiple myeloma is 15%, and clinically evident mucocutaneous involvement occurs in up to 40% of patients.     

Localized axillary milia en plaque: a rare cutaneous case presentation of systemic amyloidosis

Systemic AL amyloidosis is known to be associated with plasma cell dyscrasias, including multiple myeloma. The cutaneous manifestations of systemic AL amyloidosis are varied, but typically include waxy plaques or subcutaneous nodules. We report a woman who presented with bilateral eruptions of hyperpigmented plaques in her axillae, which were diagnosed as milia en plaque. She had a history of multiple myeloma, for which she was under the care of a haematologist. This is the first documented case, to our knowledge, of an eruption in the axillae being milia en plaque.     

Elastolytic cutaneous lesions in myeloma-associated amyloidosis

Elastolytic cutaneous lesions were the initial manifestation of amyloidosis in two patients with multiple myeloma. The skin of the fingertip was noticeably soft, loose, and redundant. The skin of the fingers was depressed with pressure and remained depressed for an abnormally long period of time. Amyloid deposition in the dermis was demonstrated in both cases. In addition, fragmentation and a decrease of elastic fibers in the dermis were observed. Possible explanations for the pathogenesis of such skin lesions were also discussed.     

Cutaneous manifestations of multiple myeloma

We report the cutaneous manifestations of multiple myeloma, using a retrospective review of 115 patients' records obtained from tumor registry files. Five patients were found to have biopsy-proved extramedullary plasmacytomas without extension from an underlying bony focus. Twelve patients had ecchymoses without thrombocytopenia; two of them had biopsy-proved amyloidosis. One patient presented with pyoderma gangrenosum and was subsequently diagnosed with multiple myeloma. The last patient initially presented with what clinically appeared to be leukocytoclastic vasculitis, and, in the course of a standard workup, he was diagnosed with multiple myeloma. These findings are discussed with regard to the current literature on the cutaneous manifestations of multiple myeloma.     

Cutaneous localization of plasmablastic multiple myeloma with heterotopic expression of CD3 and CD4: Skin involvement revealing systemic disease

Plasmablastic multiple myeloma is an uncommon morphological variant of multiple myeloma with aggressive clinical course and poor outcome. Its differential diagnosis includes plasmablastic lymphoma, a variant of diffuse large B‐cell lymphoma with frequent extranodal presentation, which usually affects immunosuppressed patients and is virtually indistinguishable from plasmablastic multiple myeloma on the basis of histology solely. Differential diagnosis relies on close clinical‐pathological correlation. Herein, the authors report a case of aggressive multiple myeloma occurring in a 48‐year‐old patient with pure plasmablastic morphology, expression of T‐cell markers CD3 and CD4, and cutaneous involvement as first presenting sign. Heterotopic expression of T‐cell markers has been described in literature for both plasmablastic multiple myeloma and plasmablastic lymphoma. The causative mechanisms underlying this aberrant phenotype have not yet been elucidated; nevertheless the possibility of this rare finding should be considered to avoid misinterpretations. Remarkably, despite occurring rarely, cutaneous involvement could be observed at an early stage or even be the first manifestation of disease in particularly aggressive forms of myeloma. As a consequence, the presence of cutaneous lesions should not favor a straightforward diagnosis of plasmablastic lymphoma. The importance of a correct differential diagnosis lies in its therapeutical implications.     

Skin location of multiple myeloma mimicking a vascular tumor]

INTRODUCTION: Cutaneous location of multiple myeloma is rare, and generally develops as a consequence of direct spread from an underlying bony focus of the disease. Metastatic skin lesions without adjacent bone involvement are uncommon. The prognosis is very poor. CASE REPORT: A 74-year-old man consulted for a hemorrhagic cutaneous nodule localized on the left inguinal area. This patient had been treated for five months for a stage I IgG lambda multiple myeloma. The histopathologic examination of the lesion showed a predominantly nodular configuration made up of masses of atypical cells with numerous hemorrhagic areas. The diagnosis of cutaneous metastasis of multiple myeloma was confirmed by the positivity of the cells for anti-IgG lambda antibodies. DISCUSSION: Cutaneous involvement in multiple myeloma without extension from underlying bony focus is exceptional. The lesions generally consist of firm, erythematous nodules involving the neck and lower extremities. To our knowledge, we present here the first case mimicking clinically and histologically a malignant vascular proliferation.     

Nail dystrophy and blisters as sole manifestations in myeloma-associated amyloidosis

We report the case of a 61-year-old Japanese man with IgG lambda-type multiple myeloma, who presented with nail dystrophy as the initial manifestation of systemic amyloidosis. Subsequently he developed bullous amyloidosis. This report documents these two rare signs of systemic amyloidosis and demonstrates the precise location of cutaneous blister formation and amyloid deposition by fluorescence antigen mapping and electron microscopy.     

小儿获得性二期梅毒1例

患儿女,4岁。外阴、肛周皮损1月余,伴虫蚀样脱发半月余。皮肤科情况:外阴、肛周可见红色湿性斑块,肛周皮损表面覆灰白色薄膜及分泌物。RPR1:32(+),TPPA(+)。诊断:小儿获得性二期梅毒。予苄星青霉素肌内注射治疗后皮损基本消退。