Paraproteinemic skin diseases D47.2

Paraproteinemias (monoclonal gammopathies) are characterized by the pathological appearance of a homogeneous immunoglobulin in the blood. A paraproteinemia without the simultaneous presence of a multiple myeloma or a plasmocytoma or another clonal lymphoproliferative disease used to be called"benign gammopathy" or "benign paraproteinemia". In recent years, the term"monoclonal gammopathy of undetermined significance" (MGUS ) has also become common for this condition.

MGUS is defined as a "disease" in which patients have a constant concentration of monoclonal immunoglobulin in their serum or urine over a prolonged period of time and are asymptomatic. The monoclonal immunoglobulin is produced by very slowly proliferating, non-malignant plasma cells in the bone marrow. In many cases, the diagnosis can only be made after prolonged observation of the course of the disease.

Skin changes in paraproteinemias (monoclonal gammopathy) can be divided into 3 groups according to Daoud MS et al:

Group I (skin lesions with specific skin infiltrates or directly related to the underlying disease):

• Lymphoma, cutaneous B-cell lymphoma, plasmocytoma.
• lymphoma, cutaneous B-cell lymphoma, Waldenström's disease
• Macroglobulinemia (see below Lymphoma, cutaneous B-cell lymphoma, Waldenström's disease)

Group II (skin lesions with hyperplastic association with paraproteinemias - paraneoplastic syndromes):

• Close association:

  • AL-typeamyloidosis

  • cryoglobulinemia (see below cryoglobulins and skin lesions)

  • POEMS syndrome

  • Scleromyxedema (Arndt-Gottron)

  • Lichen myxoedematosus
  • Scleroedema adultorum (Buschke)
  • Spiny hyperkeratosis
  • TEMPI syndrome(telangiectasias, erythrocytosiswith elevated erythropoietin, monoclonalgammopathy, perinephricfluid collections, intrapulmonaryshunt)
  • Xanthogranuloma, necrobiotic
  • xanthomas, plane
  • Schnitzler's syndrome.
• Medium association:
  • Pyoderma gangraenosum
  • Sweet syndrome
  • Vasculitis, leukocytoclastic
  • Pemphigus, IgA pemphigus.
• Association known but inconstant:
  • Erythema elevatum diutinum
  • Lupus erythematosus
  • Malum perforans (in paraproteinemic induced polyneuropathy).
  • Pustulosis, subcorneal
  • Capillary leak syndrome
  • Verrucosis paraproteinemica of the feet
  • Autoimmunological blistering skin diseases (pemphigus and pemphigoid group)

Group III (published associations without confirmed evidence):

• Acrokeratosis paraneoplastic (Bazex syndrome - published individual cases).
• Alopecia atrophicans ( pseudopélade):
• Anetoderma
• angioma serpiginosum
• Angioendotheliomatosis, reactive (benign)
• Calcinosis metastatica (in bone destruction due to multiple myeloma)
• Cutis laxa (acquired)
• Epidermolysis bullosa acquisita
• Erythema exsudativum multiforme
• Gangraena acuta genitalium (Fournier's gangrene)
• Hyalinosis cutis et mucosae
• Lichen myxoedematosus
• Mycosis fungoides (coincidence?)
• Panniculitis, histiocytic, cytophagic
• Papulosis maligna atrophicans
• Pityriasis rotunda
• Prurigo simplex subacuta (paraneoplastica)
• Purpura, dysproteinemic
• Purpura, thrombocytopenic
• REM syndrome
• Rosacea-like skin lesions
• Teleangiectasia macularis eruptiva perstans
• Ulcus cruris in multiple myeloma
• Xanthoma disseminatum.

Serum electrophoresis is recommended in all patients with markedly elevated ESR, unclear blood count changes (anemia, cytopenias), nephrotic syndrome, suspected liver cirrhosis, polyneuropathy(paraproteinemic neuropathy), altered total protein, suspected immunodeficiency.

Any paraproteinemia detected for the first time must be considered a suspected multiple myeloma/plasmacytoma/M.Waldenström until refuted! This requires the determination of immunoglobulins quantitatively in serum and urine as well as immunofixation in serum and urine. Furthermore, determination of blood count as well as creatinine and calcium (hypercalcemia) in serum.

Imaging: Sonography, CT skull, spine, pelvis and all dolent parts; possibly MRI of the spine.

Bone marrow: biopsy with aspiration cytology and cytogenetics. If necessary, molecular genetics (e.g. MYD88 mutation status).

Control program: The intensity of clinical controls depends on patient age, comorbidities, previous course. A control of the immunoglobulin fractions IgG, IgA and IgM is recommended in quarterly to half-yearly intervals; here, the quantitative measurement is sufficient, the immunofixation does not need to be repeated. In younger patients, it is also advisable to check the bone marrow findings at approximately annual intervals. Pain in the musculoskeletal system must be clarified by imaging.

Treatment is not beneficial for patients with MGUS and is therefore not indicated. However, regular monitoring of these patients with the only seemingly harmless laboratory phenomenon is of immense importance.

The indication for invasive testing is made individually depending on patient age and risk factors. The probability of occurrence of multiple myeloma increases if the other two polyclonal immunoglobulin fractions are reduced (e.g. in the case of IgG paraprotein: reduction in the concentrations for IgA and IgM), and the detection of paraprotein in the urine is also an alarm sign (usually Bence-Jones protein = light-chain portion of the immunoglobulin that passes through the kidney). Another prognostically unfavorable aspect is an increase in the amount of paraprotein over time. In senile patients with inconspicuous X-ray diagnostics and stable humoral values, it will be possible to dispense with an examination of the bone marrow.

Long-term follow-up has shown that most patients with MGUS remain asymptomatic, but 10-15% develop malignant B-cell disease after an observation period of 5 years, and of these, more than half develop multiple myeloma.

In the course of 10 years 16%, after 20 years already 33% of the MGUS cases develop into a malignant lymphoproliferative disease! Most of these are multiple myelomas. More rarely, Waldenström's disease (in the case of paraproteinemia of the IgM type), amyloidosis or malignant non-Hodgkin's lymphoma develop.

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