Dermatology Online Journal

Multiple myeloma presenting as a novel mucocutaneous eruption
David N Lortscher MD¹, Stan A Amundson MD², Mark R Pittelkow MD³
Dermatology Online Journal 16 (12): 4

1. University of California, San Diego, San Diego, California. dlortscher@gmail.com
2. Scripps Mercy Hospital, San Diego, California
3. Mayo Clinic, Rochester, Minnesota

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Abstract

A 71-year-old woman presented with exquisitely tender mucosal erosions, a diffuse polymorphous eruption, and night sweats. Workup revealed multiple myeloma with a monoclonal IgG-kappa paraprotein in the serum. Her severe oral involvement was suggestive of paraneoplastic pemphigus, but direct and indirect immunofluorescence tests were negative. A skin biopsy showed spongiosis and a sparse perivascular lymphocytic infiltrate, with occasional CD8-positive lymphocytes in the epidermis. Her lesions improved with intravenous immune globulin. Immunohistochemical staining on the formalin-fixed biopsy specimen was strongly positive for IgG and IgG-kappa in an epidermal “chicken-wire” pattern, but negative for IgG-lambda. Her pulmonary tissue stained negative for IgG-kappa, suggesting clinical relevance of the myeloma paraprotein in her epidermis. To our knowledge, this is the first report of a multiple myeloma patient with such an eruption.

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Introduction

Multiple myeloma is a hematologic malignancy characterized by a clone of bone marrow-derived plasma cells that produce monoclonal immunoglobulin. We report the case of a woman who was found to have multiple myeloma after she presented to the emergency department with severe mucositis and a generalized skin eruption.

Report of a case

An active 71-year-old woman with a history of hypertension and hypothyroidism presented for a new pruritic eruption covering most of her body including the palms, soles, mouth, and nares. The lesions in the mouth and nares were exquisitely painful to the point that she could only sip liquids in small amounts through a straw. Review of systems was positive for night sweats and unintended weight loss.

Figure 1a	Figure 1b
Figure 1a. Crusted erosions in the mouth and nose. Figure 1b. Red-to-violaceous macules and papules.

Her oronasal mucosae were covered with erosions and crusts and her trunk and extremities had polymorphic macules and papules. The palms and soles were involved with blanchable, erythematous macules.

Laboratory workup revealed anemia, thrombocytopenia, and a monoclonal spike of immunoglobulin G (IgG) kappa in the blood and urine. Her bone marrow was hypercellular with greater than 90 percent atypical plasma cells, confirming the diagnosis of multiple myeloma. Other laboratory studies were unremarkable, including an extensive workup for autoimmune and infectious diseases.

Figure 2
Figure 2. Spongiosis, a sparse perivascular lymphocytic infiltrate, and occasional lymphocytes in the epidermis (H&E, x20)

Skin biopsy showed spongiosis and a sparse perivascular lymphocytic infiltrate; there were occasional lymphocytes in the epidermis, most of which were positive for CD8, and there was no plasma cell infiltrate. Clinically, her severe oral involvement was suggestive of paraneoplastic pemphigus, but direct immunofluorescence was negative and indirect immunofluorescence showed no reactivity of the patient’s serum with rat bladder epithelium.

The patient was empirically started on intravenous methylprednisolone (125 mg BID), with resolution of the skin lesions but no change in the mucosal lesions. A week later, intravenous immunoglobulin was started (0.2 gm/kg/day) for five days, with dramatic improvement of her oral and nasal lesions.

Her course was complicated by dyspnea and increasing oxygen requirements. Bronchoscopic lung biopsy showed intra-alveolar accumulation of a thin, eosinophilic, proteinaceous material, consistent with pulmonary alveolar proteinosis, a lung condition that has been associated with multiple myeloma. The patient declined transfer to the intensive care unit and soon after she died from respiratory failure.

Discussion

We report the case of a previously undiagnosed multiple myeloma patient who presented with a rash of unclear etiology. The clinical appearance was suggestive of paraneoplastic pemphigus, given that she had a known hematologic malignancy, a severe refractory stomatitis, and a workup that did not reveal any other cause of her mucocutaneous disease. However, direct and indirect immunofluorescence tests were both negative for autoantibodies, eliminating classic paraneoplastic pemphigus as a possible diagnosis [1].

Figure 3a	Figure 3b
Figure 3. There is positive staining for IgG and IgG-kappa (a and b), but not for IgG-lambda (c) (immunohistochemistry, original magnification x40).

Figure 3c

Because of the temporal relationship of the skin findings with her diagnosis of multiple myeloma, immunohistochemical staining was performed to evaluate for evidence of IgG-kappa paraprotein in the skin. Immunostaining on the formalin-fixed biopsy specimen was strongly positive for IgG and IgG-kappa in an epidermal “chicken-wire” pattern, and negative for IgG-lambda. As a control, the same IHC stains were performed on the patient’s lung biopsy tissue and they were negative. The presence of antibodies in the skin but not in the lungs suggests a possible causative role for the antibodies in the patient’s mucocutaneous disease.

It appears inconsistent that epidermal IgG-kappa was demonstrated with immunohistochemistry but was not seen on immunofluorescence. We suspect that the paraprotein was specific for an unknown epidermal cell surface antigen, but that the affinity was much weaker than that typically seen in a polyclonal immune disease such as pemphigus vulgaris or paraneoplastic pemphigus. Thus, the autoantibodies were detectable upon staining of the formalin-fixed, paraffin-embedded biopsy tissue, but the antibodies washed off during direct immunofluorescence studies (performed on fresh skin tissue) and during indirect immunofluorescence (performed with the patient’s blood).

Typically, immunofluorescence is performed to diagnose autoimmune disease mediated by polyclonal autoantibodies to a specific antigen in the skin. For example, the autoantibodies in paraneoplastic pemphigus represent an antigen-specific polyclonal response that may be induced by immune dysregulation or by epitope spreading [2, 3]. In contrast, a patient with multiple myeloma produces a monoclonal antibody that may or may not have an affinity of any strength for any given antigen. We suspect that our patient’s paraprotein had a weak affinity for an epidermal cell-surface antigen and that the antibody led to her symptoms by an unclear humoral mechanism in combination with a CD8-lymphocyte-mediated cellular immune response.

Multiple myeloma has previously been associated with a wide variety of cutaneous manifestations including purpura, vasculitis, cryoglobulinemia, amyloidosis, plasmacytoma, scleromyxedema, scleredema, and Sweet syndrome [4, 5]. Our patient presented with skin findings that may have been caused by deposition of myeloma paraprotein in the epidermal intercellular space. To our knowledge, there have been no previous reports of a similar eruption in a patient with multiple myeloma.

References

1. Anhalt GJ, Kim SC, Stanley JR et al. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med 1990; 323: 1729-35. [PubMed]

2. Nousari HC, Kimyai-Asadi A, Anhalt GJ. Elevated serum levels of interleukin-6 in paraneoplastic pemphigus. J Invest Dermatol 1999; 112: 396-8. [PubMed]

3. Bowen GM, Peters NT, Fivenson DP et al. Lichenoid dermatitis in paraneoplastic pemphigus: a pathogenic trigger of epitope spreading? Arch Dermatol 2000; 136: 652-6. [PubMed]

4. Bayer-Garner IB, Smoller BR. The spectrum of cutaneous disease in multiple myeloma. J Am Acad Dermatol 2003; 48: 497-507. [PubMed]

5. Daoud MS, Lust JA, Kyle RA, Pittelkow MR. Monoclonal gammopathies and associated skin disorders. J Am Acad Dermatol 1999; 40: 507-35. [PubMed]

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