Myeloma, Paraproteinemias, and the Skin

Cutaneous Oncology

Myeloma, Paraproteinemias, and the Skin Warren W. Piette, MD.*

The correct and timely diagnosis of benign and malignant neoplastic plasma cell disease can be one of the most difficult challenges facing any clinician, no matter what his chosen field. The clinical manifestations are often insidious in onset, the signs and symptoms misleading, and the laboratory alterations subtle. The protean clinical presentations of plasma cell dyscrasias may be due to malignant plasma cell proliferation, leading to tissue or organ compromise, or due to abnormal quantity or quality of an elaborated monoclonal protein. Monoclonal protein production can result in cold agglutinin disease,72, 80 hyperviscosity syndromes,63, 80 and monoclonal or mixed cryoglobulinemia,lO, 28, 58, 80 all of which may have striking cutaneous findings and are reviewed elsewhere. Plasma cell disorders may also present in association with other disease processes, making the correct diagnosis even more difficult to determine. Finally, while perhaps less "benign" than previously thought, the presence of a monoclonal spike on serum protein electrophoresis may be an unrelated laboratory finding, incidentally discovered in the course of evaluating a patient's complaint. 54 This review will focus on those systemic diseases or syndromes in which the cutaneous findings may be important clues to the correct diagnosis of a plasma cell disorder, and on those cutaneous diseases which appear to have a greater than chance association with monoclonal plasma cell proliferation. Especially emphasized will be the cutaneous manifestations of amyloidosis, the POEMS syndrome, cutaneous plasmacytomas, certain xanthomatous disorders, benign hypergammaglobulinemic purpura of Waldenstrom, and scleromyxedema. AMYLOID FIBRIL-RELATED DISEASE (P FIBRILLOSES)

There are a variety of clinical disorders that either result in or are the result of the tissue deposition of amyloid fibrils. 24, 32 As understanding of amyloid fibril-related syndromes has increased, older classifications have *Assistant Professor of Dermatology, University of Iowa Hospitals and Clinics, Iowa City, Iowa

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been revised, and identification of the fibril type has been emphasized. In one recent classification,32 the [3-fibrilloses have been divided into three major groups: acquired systemic amyloidosis, organ-limited amyloidosis, and localized deposition of amyloid. Acquired systemic amyloidosis has been subdivided into immunocyte dyscrasias with amyloidosis (light-chainderived or AL-fibril type), reactive systemic amyloidosis (protein Aderived or AA-fibril type), and heredofamilial systemic amyloidosis. Important cutaneous aspects of disease will be considered within the framework of this classification system. Acquired Systemic Amyloidosis: AL Type The light-chain-derived (AL) systemic amyloidoses have been most extensively studied in the setting of primary systemic amyloidosis and myeloma-associated diseases. Peripheral neuropathy, carpal tunnel syndrome, orthostatic hypotension, congestive heart failure, and nephrotic syndrome are prominent features of AL amyloidosis. In one large series of 229 patients with AL amyloidosis, 57 21 per cent had associated multiple myeloma, and 89 per cent of the 216 patients appropriately examined had a monoclonal protein present in serum or urine. The incidence of cutaneous lesions in AL-derived systemic amyloidosis ranges from 21 to 25 per cent, 55 to 29 per cent,78 to 40 per cent. 9, 11 Purpura, papules, plaques, and nodules are the most common lesions; bullous eruptions (occasionally mimicking porphyria cutanea tarda or epidermolysis bullosa acquisita), a scleroderma-like skin infiltration, pigmentary changes (including jaundice, pallor, erythema, and hyperpigmentation), nail dystrophies, and alopecia are less common. 9, 11; 15, 55, 57, 69. 78 Purpura is the most common finding; it may result from several factors, including amyloid infiltration of the vessel wall,15 an acquired factor-X deficiency,30, 36 and possibly lowered levels of the vitamin K-dependent factors IX, VII, and 11, increased antithrombin activity, and increased fibrinolysis. 36 Purpura can often be induced by gentle pinching or stroking of lesions or even clinically normal-appearing skin, especially around the eyes; in fact it can be used as a diagnostic sign. Periorbital purpura may also follow coughing, vomiting, other Valsalva-like maneuvers, and dependency of the head, especially during proctoscopy. Papules and plaques are most often smooth, yellow to skin colored, translucent to waxy, nonpruritic, nontender, and frequently slightly hermorrhagic (Fig. 1). Typical sites of papular involvement due to amyloid deposition include the central face and eyelids, lips, tongue, buccal mucosa, and intertriginous areas, such as behind the ears, on the neck, or in the axillary, inguinal, anogenital, and periumbilical regions. Nodules may occur at any site, and may occasionally resemble xanthomas or condylomata lata.!1 Rarely, amyloid deposition may present as proptosis or ophthalmoplegia. 76 Involvement of lacrimal and parotid glands may result in a presentation resembling keratoconjunctivitis sicca or Sj6gren's syndrome. 33, 84 The incidence of macroglossia ranged from 12 to 40 per cent in several series, 11, 55, 57 often with lateral margin dental indentations and a smooth and dry surface. Recurrent hemorrhagic bullae of the oral cavity are common, and papules may occur on the tongue, buccal mucosa, or floor of the mouth. 29, 57 Infiltration of the shoulder region by

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Figure 1. puric areas.

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AL-derived systemic amyloidosis. Waxy papules on anterior chest, with pur-

amyloid may produce severe pain and swelling and massive soft tissue enlargement ("shoulder pad sign"),43 or weakness and pseudohypertrophy of skeletal muscles. 93 Rarely, dermatomyositis has occurred in association with apparent AL-amyloidosis. 97 A biopsy of such clinical lesions in AL-derived systemic amyloidosis should provide diagnostic evidence of amyloid deposition. More importantly, even in patients without obvious cutaneous involvement, a punch biopsy of the skin may reveal amyloid deposits. Yields of 47 per cent and 50 per cent have been obtained by biopsy of clinically normal skin in two series of primary systemic amyloidosis patients. 15, 78 The skin biopsy of an amyloid papule usually shows deposits in the superficial dermis, infiltration of dermal vessel walls by amyloid, and often thinning or loss of rete ridges (Fig, 2), in contrast to the pattern expected for localized cutaneous amyloidosis (Fig. 3). Amyloid deposits may compress the follicles, resulting in atrophy and hair loss. Congo red staining with green birefringence in polarized light is the most specific nonimmunologic stain for amyloidosis, though methyl violet, crystal violet, and occasionally thioflavine T may be useful in screening biopsies. Acquired Systemic Amyloidosis: AA Type Protein A-derived amyloidosis (AA-fibril type) is often referred to as secondary or reactive amyloidosis. Organ infiltration is classically seen in the liver, kidney, and spleen, but any organ may be involved. Amyloid deposition in this setting generally occurs in association with a chronic inflamatory process, such as rheumatoid arthritis, tuberculosis, leprosy, syphilis, chronic osteomyelitis, and chronic inflammatory bowel disease. Amyloidosis may be associated with certain dermatoses: chronic decubitus ulcers, stasis ulcers, thermal burns, long-standing basal cell carcinoma,

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Figure 2. Biopsy of cutaneous papule in AL amyloidosis. There is mild epidermal atrophy, loss of rete ridges, diffuse dermal deposition of amyloid, and amyloid infiltration of the walls of dermal vessels.

Figure 3. Biopsy of cutaneous papule in lichen amyloidosis. There are prominent, elongated rete ridges surrounding papillary-tip amyloid deposits , with absence of vessel wall infiltration by amyloid.

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hidradenitis suppurativa, dystrophic epidermolysis bullosa, psonasIs, psoriatic arthritis, and Reiter's syndrome. 7, 13 A more recent report implicates nodular non supportive panniculitis as a caue of reactive amyloidosis in" one patient. 73 Clinically apparent skin lesions caused by amyloid deposition in AA amyloidosis are quite rare; the most common cutaneous manifestation is nonpalpable purpura. The rarity of skin lesions stands in marked contrast to the incidence of skin lesions in AL systemic amyloidosis, and suggests that if a patient with suspected systemic amyloidosis is shown to have a skin lesion due to amyloid deposition, the amyloid is almost certainly of the AL type. Despite the rare clinically apparent lesion in AA amyloidosis, a biopsy of apparently normal skin may yield evidence of amyloid deposition in 7 to 42 per cent of patients. 15, 78 In contrast to AL amyloidosis, involvement by AA amyloid tends to be deep in the dermis around the adnexa, in the subcutaneous fat, and occasionally around small vessels in lower dermis and fat. Because of the depth of the deposits, fine-needle aspiration biopsy of subcutaneous abdominal fat has been used in patient populations at high risk for developing AA amyloidosis;86 the same procedure has been used more recently in evaluating 32 consecutive cases of systemic amyloidosis. 60 Needle aspiration diagnosis appears to be a suitable screening method, with high yield in known amyloidosis (88 per cent overall), but it is possible that false-positive results may occur. For example, examination of urinary sediment for amyloid fibrils, originally felt by some to be a specific finding, was found to be nonspecific when control samples were studied. 95 The true incidence of false positives may require an investigation of nonamyloidosis, non-rheumatoid arthritis control populations. Acquired Systemic Amyloidosis: Heredofamilial Types A number of familial syndromes of amyloidosis have been described among different kindreds. Familial Mediterranean fever is inherited in an autosomal recessive fashion; some patients with this disease develop AAfibril amyloidosis, similar to that previously described. The remainder of the syndromes thus far described are inherited in an autosomal dominant fashion and probably are the result of a non-AA amyloid fibril deposition. Many of the syndromes have in common peripheral polyneuropathy, autonomic nervous system dysfunction, and varying involvement of the heart, gastrointestinal tract, and eyes (with scalloping of pupils). Skin involvement in these patients has not been prominent in previous reports, except for the report of Rubinow and Cohen, who evaluated 11 patients from five different kindreds with familial amyloidosis. 79 Four patients had multiple atrophic scars and poorly healed ulcers, and two had petechiae induced by stroking the skin. A 3-mm punch biopsy of clinically normal forearm skin was positive in all 11 patients with known amyloidosis. Histopathologic study demonstrated involvement of the sweat glands in all instances, frequent involvement of the arrector pili and the dermis, and occasional involvement of blood vessel walls. The histologic pattern was similar to that seen with reactive or AA amyloidosis. With the use of fine-needle abdominal fat aspiration, six of seven patients with heredofamilial amyloidosis had positive biopsies. 60 While the fibril type is not known for all

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familial amyloidoses, at least six different kindreds have been shown to have prealbumin as the major component of their amyloid fibrils. H. 59. 82 Prealbumin is so named for its electrophoretic migration in serum protein electrophoresis; it is not an albumin precursor. It is perhaps more properly termed plasma transthyretin (TTR), and is important in the transport of both thyroxine and retinol. Four transthyretin molecules form a tetrameric ring, with a binding site for thyroxine in the center, and usually one bound complex of retinol and retinol-binding protein (RBP) on the outside of the ring.35 Since TTR (or prealbumin) and RBP are usually associated in the serum, investigators have examined the serum levels of these compounds in affected patients. In one study, in which patients with the Portuguese type of familial amyloidosis were examined, significantly reduced levels of TIR and normal levels of retinol and RBP were found, and the TIR present did not appear to be abnormal. 82 In an Indiana kindred offamilial amyloidosis, both TIR and RBP levels were significantly reduced in affected patients. 52 The significance of these findings is unknown, but the physiologic roles of retinol and retinoic acid are being actively explored in conjunction with the synthesis of new retinoid compounds, and some immunologic effects have been attributed to retinol itself. The Muckle-Wells syndrome was first described in 1962 as a heredofamilial syndrome of urticaria, deafness, and amyloidosis. This syndrome classically involves: (1) periodic attacks of fever, chills, rigors, and malaise, accompanied by limb pains and an urticarial skin rash; (2) progressive perceptive deafness; and (3) nephropathy due substantially to amyloid deposition. 6i The urticarial papules are relatively flat and geographical and are symptomatic (aching or sore, and rarely pruritic). The febrile attacks last 12 to 36 hours and recur with variable intensity every few weeks. In the original family, the disease was clearly inherited in an autosomal dominant fashion. Polyclonal hypergammaglobulinemia and an elevated erythrocyte sedimentation rate persist between attacks. Amyloidosis is not an invariable feature of the disease and may be related to the recurrent inflammatory bouts. The fibril type is unknown. Organ-Limited Amyloidosis: Skin There are four principal cutaneous types of organ-limited amyloidoses: lichen amyloidosis, macular amyloidosis, localized amyloid deposition around or within certain epidermal and dermal growths, and nodular or tumefactive cutaneous amyloidosis .14. 38, 52 Pruritic eruption is the clinical manifestation of lichen amyloidosis, The individual lesions are domeshaped, firm, nontender, hyperkeratotic papules, varying in col or from flesh-calored to slightly yellow, brown, or gray. The anterior lower extremities are the most common sites but often the upper extremities and occasionally the shoulders, chest, abdomen, or sacrum may also be involved. Some cases are familial. Histopathological examination of a lesion reveals amyloid deposition in the papillary tips, without involvement of vessel walls. In contrast to the changes seen with AL-associated amyloidosis, there is a lJ1inimal infiltrate; and the rete ridges may be elongated and displaced laterally (see Fig. 3). The lesions of macular amyloidosis are oval or poorly delineated

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hyperpigmented macules that often have a grayish brown tint; this form of amyloidosis is probably a variant of lichen amyloidosis. The lesions are usually pruritic, in contrast to systemic amyloidosis lesions, and the pruritus may precede obvious clinical involvement. The lower extemities are the most common site of involvement; occasionally the back may be the first site involved. Histopathological examination shows changes that are similar to, but less marked than, those seen in lichen amyloidosis. Certain cutaneous lesions or tumors are occasionally found to have amyloid deposited around or within them. Most commonly these lesions are actinic keratoses, basal cell carcinomas, Bowen's disease (carcinoma-insitu), and seborrheic keratoses. Nodular or tumefactive localized cutaneous amyloidosis may present as nodules on the face, extremities, trunk, or genitals. On biopsy examination, there is usually an atrophic overlying epidermis. The amyloid infiltration is seen in the dermis and subcutaneous fat, as well as occasionally in the walls of large blood vessels. Plasma cells, giant cells, and foci of calcification may also be seen.14 While some patients with localized nodular cutaneous amyloidosis may never develop signs of extracutaneous involvement, 5 of 10 patients in one series ultimately developed signs of systemic amyloidosis.1 4 The amyloid fibril in lichen amyloidosis, macular amyloidosis, and tumor-associated amyloidosis is derived largely from keratin; some have proposed naming the material K amyloid. 38 Nodular cutaneous amyloid does not appear to be keratin-derived, though its exact etiology is unknown. 38 THE POEMS SYNDROME

First described as a unique syndrome in Japan in 1968, the POEMS syndrome is also known as the PEP, Crow-Fukase, or Takatsuki syndrome. 5, 45, 70 The acronym POEMS stands for polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin lesions. A recent comprehensive review of 102 Japanese cases of this syndrome noted a male to female ratio of 2:1 and a mean age of onset of 46, with 25 per cent of patients younger than age 40 at presentation. Peripheral polyneuropathy is a cardinal feature of this syndrome, occurring in 100 per cent of 102 patients. It is usually a progressive, sensorimotor polyneuropathy, with only 3 per cent of patients having a pure motor defect. Sixty-two per cent of patients had papilledema, and 97 per cent had elevated cerebrospinal fluid protein. 70 In one series of 16 patients, the patients had neurologic symptoms for a median of 20 months before diagnosis, and though all 16 patients had osteosclerotic myeloma, only one was diagnosed before a workup for cryptogenic peripheral neuropathy. 45 Organomegaly is an important finding, with hepatomegaly occurring in 82 per cent and splenomegaly occurring in 39 per cent of the patients. Lymphadenopathy also occurs in 65 per cent of POEMS patients; the most common pathologic findings on node biopsy consisted of arborizing capillaries in follicular centers, capillary proliferation and sheets of mature

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plasma cells in the interfollicular tissue, and clear-cut lymph sinuses with sinus histiocytosis. 70 Endocrine abnormalities are frequently found, especially gynecomastia (68 per cent) and impotence (78 per cent) in men and amenorrhea (68 per cent) in women. 70 In two patients with hypogonadism, gonadotropins were high, suggesting primary gonadal failure. 5 Hyperprolactinemia was also noted in these two patients. Glucose intolerance has been found in 28 to 48 per cent of patients 5. 70 and hyperthyroidism in 10 to 24 per cenPO Adrenal insufficiency and hypercalcemia have also occurred. 70 A monoclonal protein has been found in the serum or rarely in the urine in 75 per cent of patients,70 but the amount tended to be small. 45 Not all patients with this syndrome and an M-spike have progressed to definite myeloma, even after many years.70 In the largest series, 95 per cent of patients had a A. light chain component in their monoclonal proteins, with 54 per cent having IgG A., 41 per cent IgA A., 4 per cent IgA K, and 1 per cent IgG K. 70 Two of these patients had only an extramedullary plasmacytoma. Unlike the findings in osteolytic multiple myeloma, anemia, hypercalcemia, and renal insufficiency are uncommon,45 and bone marrow infiltration by plasma cells is rare. 5. 45. 70 Skin changes are commonly seen in this disorder, the most frequent being diffuse hyperpigmentation, which is present in 93 to 98 per cent of the patients, apparent skin thickening, found in 77 to 85 per cent of patients, and hypertrichosis, a finding with a 78 to 81 per cent incidence. 5. 70 However, the skin thickening was described adequately in only two patients, whose skin was not tough or bound down, though it appeared tight. 5 Biopsy of the skin in these two cases revealed pigment deposition in the superficial dermis, but no inflammation or obvious proteinaceous material in the fat or muscle, despite a feeling of firmness to the deeper tissue. No specific mention of a mucin stain was made. There were no changes of a dermal arteriolar vasculopathy, as reported by others. Peripheral edema sometimes appearing as anasarca is very commonly seen (91 to 92 per cent incidence), perhaps accounting for sorpe of the apparent skin thickening. In relationship to this, ascites is reported in 62 to 68 per cent of patients, and pleural effusion in 24 to 40 per cent of patients. 5. 45. 70 Less common cutaneous findings include digital clubbing (56 per cent incidence),70 white fingernails (unclear if there is leukonychia or nail bed pallor), and verrucous angiomata. 5 Instances of Raynaud's phenomenon have been reported,5 and at least one patient with sicca syndrome and parotid swelling has been described. 70 Contractures of digital flexor tendons are seen, but are thought to be secondary to the upper extremity polyneuropathy. Slightly more than half the patients with POEMS syndrome had bone lesions, mostly involving the spine, pelvic bone, and ribs. Eighty-five per cent of the patients with myeloma and this syndrome had osteosclerotic or sclerotic and lytic lesions, in contrast to large series of cases of myeloma in which patients with osteosclerotic lesions make up only 0.5 to 3.0 per cent of the total. 5. 45. 70 The patients with osteosclerotic lesions, when compared to those patients with lytic lesions and the POEMS syndrome, presented at an earlier age and had a larger number of solitary skeletal lesions, a

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lower incidence of increased plasma cell infiltration on bone marrow studies, and a higher incidence of organomegaly. 70 Spiculated areas of ossification have also been reported, particularly at sites of ligamentous and capsular attachments along the spine. 5 Miscellaneous findings are multiple, but some of the more frequently seen are mild fever, polycythemia, leukocytosis, thrombocytosis, and an elevated erythrocyte sedimentation rate.·5, 45, 70 Though the mechanisms involved in the induction of these findings are not at all clear, surgical removal of extramedullary plasmacytomas, radiation therapy for isolated osteosclerotic lesions, and prednisolone alone or combination chemotherapy have all sometimes led to marked improvement in the neuropathy, hyperpigmentation, edema, and other findings, though improvement is often only temporary. CUTANEOUS PLASMACYTOMAS Cutaneous plasmacytomas occur rarely; they are almost never seen in the absence of systemic plasma cell disease. I, 17,83,85 Regardless of the setting, most cutaneous plasmacytomas present as smooth, nontender, domeshaped cutaneous or subcutaneous nod'ules, 1 to 5 cm in diameter. The lesions are flesh-colored to violaceous, and may occasionally be crusted, ulcerated, or more plaquelike. A cystic cutaneous plasmacytoma has been cited as the presenting sign in a patient with myeloma. 71 The most common sites for lesions are the trunk, the extremities, and the face. I, 83 Histological examination of a cutaneous plasmacytoma usually reveals a dense infiltrate of plasma cells in both the dermis and the subcutis with varying degrees of atypia and little or no admixture of other cell types. l , 94 Touch preps may occasionally provide the clue to the correct diagnosis, as morphology on routine tissue sections may be misleading. 34, 96 Cutaneous plasmacytomas are reported to occur in association with plasma cell leukemia,8,s but more commonly develop during the course of multiple myeloma. Lesions may develop either as a direct extension from underlying bone I, 71, 85 or more frequently as metastatic cutaneous involvement. 1 Plasmacytomas usually occur late in the course of multiple myeloma, usually indicate a poorer prognosis, and may develop in relation to total-body tumor mass. I All immunoglobulin classes except IgE have been associated with cutaneous plasmacytomas. 83 It has been suggested that IgA-producing plasma cell neoplasms, when compared to the relative frequencies of IgG and IgA myeloma, represent a disproportionately high percentage of cutaneous plasmacytomas,45 and perhaps an even higher percentage of plasmacytomas that have no clear-cut evidence of myeloma at presentation. 83 However, no adequately detailed series of sufficient numbers has addressed this question. This issue is more clear with respect to IgD myeloma. It accounted for only 1.5 per cent of cases of myeloma in one series,39 compared to approximate incidences of IgG of 53 per cent, IgA of 22 per cent, and Bence-Jones protein of 20 per cent. This myeloma was associated with a 63 per cent incidence of extraosseous involvement, compared to 10 per cent in light chain myeloma, 3 per cent in IgG myeloma,

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and 1 per cent in IgA myeloma. 39 With respect to cutaneous involvement, other authors reviewing IgD myeloma found that 12 of 65 patients examined had subcutaneous plasma cell infiltrates originating from osseous foci, and another 4 of these 65 patients had isolated cutaneous infiltrates. 41 A case report of multiple cutaneous plasmacytomas in a patient with IgD myeloma details some of the clinical and pathologic cutaneous findings in this condition. 34 Other striking features noted in IgD myeloma include a male predominance (76 per cent), 39, 41 a younger age at presentation,39, 41 a predominance of a >.. light chain component of the monoclonal protein (90 per cent),39, 41 a more aggressive course, 39, 41 and a higher incidence of osteolytic lesions,39 hypercalcemia,39 renal failure, 39, 41 heavy Bence-Jones proteinuria,39, 41 and amyloidosis. 41 With regard to extramedullary plasmacytomas (EMP) in general, Wiltshaw has pointed out that EMP differs from multiple myeloma and solitary myeloma of the bone by a marked preference for upper airways, a high incidence of metastatic spread to soft tissues, a frequent but random involvement of bones despite rare extensive involvement of bone marrow, a prolonged survival following local treatment in some cases, and perhaps a longer remission following therapy in most cases. 94 Four per cent of the patients in his series had skin or subcutaneous lesions at presentation, and 9 per cent eventually developed such lesions regardless of the site of presentation. Knowling et al. provide supporting evidence for a distinction between EMP and solitary plasmacytoma ofbone. 48 Solitary cutaneous plasmacytomas may be an isolated finding or may occur in the setting of multiple myeloma, while multiple cutaneous plasmacytomas are almost always associated with multiple myeloma. I, 83. 85, 94 In rare instances the skin lesions may precede the development of obvious myeloma by months, or death may occur from extramedullary involvement without any evidence of marrow plasmacytosis. 17 In a few cases, long-term disease-free survival following local therapy has been reported for patients with a solitary cutaneous plasmacytoma, 85 and in one case at least 13 years of disease-free survival followed local radiation therapy to the involved skin and hand, epitrochlear, and axillary nodes of an affected patient. 48 Another patient has been described as apparently disease-free for 2 years following local radiation therapy, despite the fact that his cutaneous plasmacytoma occurred by direct extension from a solitary underlying sternal lesion. 20 Therapy of cutaneous plasmacytomas in the setting of multiple myeloma includes chemotherapy and often lesional radiation therapy. Therapeutic decisions in cases of cutaneous plasmacytoma should be made after a thorough search for underlying multiple myeloma. Traditionally, surgical excision or irradiation has been used but in at least some cases the lesions may be quite resistant to x-ray therapy.l7, 85 NECROBIOTIC XANTHOGRANULOMA WITH PARAPROTEINEMIA

A recently described syndrome, necrobiotic xanthogranuloma with paraproteinemia has a distinctive clinical and pathologic presentation. 23, 50

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A cardinal feature of this disease is the periorbital localization of superficial yellowish plaques with telangiectasia, violaceous plaques, or deeper fleshcolored nodules, all of which tend to ulcerate and heal with scar formation (Fig. 4). These same lesions may also develop on the trunk or proximal limbs, especially the flexural areas. Two patients had definite multiple myeloma, one had a lymphoproliferative process found on bone marrow biopsy, and two had bone marrow proliferation with atypical plasma cells. Conjunctivitis, keratitis, uveitis, iritis, and proptosis were also seen; blindness occurred in two patients. Infrequent findings included cryoglobulinemia, Raynaud's phenomenon in a patient with significant cryoglobulinemia, leukopenia, hyperlipidemia, and diabetes mellitus. Examination of a biopsy of such lesions reveals extensive replacement of the dermis and subcutis by confluent granulomas, with foamy histiocytes, foreign body and Touton giant cells, and prominent zones of necrobiosis. Of the 10 patients described thus far, all have had an associated monoclonal protein (IgG K in five and IgG X. in three of these patients in whom immunoelectrophoresis was also performed). The differential diagnosis includes primarily necrobiosis lipoidica diabeticorum and also other xanthomatous and xanthogranulomatous processes, but the clinical setting as well as the pathologic findings are characteristic enough to allow ready recognition of this syndrome. Therapy with high-dose prednisone, intralesional triamcinolone injections, and cytotoxic agents has been variably effective, apparently in patients both with and without myeloma.

XANTHOMAS Xanthoma disseminatum is a histiocytic proliferative disorder of unknown etiology that appears to be associated with an increased incidence of monoclonal gammopathy and multiple myeloma. 6, 62 Though the disease may begin at any age, approximately two thirds of reported patients have presented before 25 years of age. 62 Men are affected more frequently than women. 6, 62, 64 The cutaneous lesions vary in morphology from papules and

Figure 4. Necrobiotic xanthogranuloma with paraproteinemia. Xanthomatous involvement of periorbital area, with erosion, ulceration, and scarring.

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nodules distributed primarily in the flexural and intertriginous areas (Fig. 5). Their color may be yellow, yellow-brown, reddish purple, or mahogany.6. 62. 64 Xanthelasma is often present. 62 Oral cavity and upper airway lesions are present in up to 40 per cent of patients, 6, 53. 62, 64 and their presence may cause dysphagia, dyspnea, or rarely asphyxiation,6 The conjunctiva and cornea may be involved in up to 20 per cent of patients. Transitory diabetes insipidus is found in up to 40 per cent of patients. Serum lipid levels are usually normal. 62 One patient developed both cystic and lytic bone lesions, resembling somewhat those seen in Gaucher's disease and multicentric reticulohistiocytosis, respectively.64 Routine histologic examination of early lesions has shown proliferation of nonfoamy histiocytes. Later lesions contain foamy and nonfoamy histiocytes, a moderate number of inflammatory cells, fibroblasts, and Touton giant cells with apparent secondary accumulation of lipids. A variant of this disorder, disseminated xanthosiderohistiocytosis, differs primarily by a tendency toward angularbordered, keloidal lesions and a more cephalad lesion distribution clinically, and extensive fibrosis and hemosiderin deposits histologically.6 Electron microscopy has failed to identify Langerhans-cell granules in the proliferating histiocytes. 6, 53 Therapy for xanthoma disseminatum has been largely unsuccessful, but clofibrate administration has been associated with control of the diabetes insipidus in two patients 53 , 64 and regression of cuta-

Figure 5. Xanthoma disseminatum. Multiple, yellowish brown papules in axillary area.

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neous lesions in another.64 In another patient, prednisone and methotrexate seemed to effect improvement in cutaneous lesions following an ineffective 8-month course of clofibrate. 6 Generalized plane xanthomatosis has also been associated with multiple myeloma. 49 • 61, 66 Plane xanthoma is a term applied to yellow to yellowbrown, slightly elevated, flat plaques composed ·of foam cells and histiocytes that are spread diffusely throughout the dermis. Localized plane xanthomas occur frequently on the eyelids; in this location they are identical to xanthelasma. Generalized plane xanthomas are much less common, however, and usually involve the head, eyelids, neck, and upper trunk and occasionally the extremities and scars (Fig. 6). Of 22 instances of generalized xanthomatosis and myeloma cited in one review, 15 cases were of the plane type. 66 Of these 15 patients, one third were normolipemic and the remainder were variably hyperlipemic, usually with combined cholesterol and triglyceride elevations. 66 The hyperlipemic patients did not have the familial history or significant atherosclerotic disease typical of familial hyperlipemic syndromes and were thought to have acquired hyperlipemia,66 The xanthomatosis usually antedated the onset of myeloma (in one case by 18 years) or occurred simultaneously with the presentation of myeloma. Some of the xanthomas were also purpuric in the absence of amyloid infiltration or obvious coagulation defects ,66 The relationship of the hyperlipemia to xanthoma formation is unclear in generalized plane xanthoma-

Figure 6. Diffuse planar xanthoma. Temple and upper lid involvement.

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tosis, since many patients are normolipemic, and since multiple myeloma is known to be a cause of acquired hyperlipidemia, even in the absence of xanthoma formation. 66 There are several reports of a monoclonal protein acting as an antilipid or antilipoprotein antibody in multiple myeloma or monoclonal gammopathies. 49 Some investigators feel that this entity is a disease 'of histiocyte' proliferation, 61 and note that the incidence of leukemia and non myeloma lymphoproliferative disease is also increased. The development of generalized plane xanthoma, especially in a normolipemic patient, is definitely an indication for a thorough investigation 'for myeloma, leukemia, or lymphoma. BENIGN HYPERGAMMAGLOBULINEMIC PURPURA OF WALDENSTROM

This syndrome, which has a female predominance, is characterized by recurrent, flat, petechial or small pupuric lesions on the lower extremities in association with a polyclonal hypergammaglobulinemia (Fig. 7).10,40,56 The lesions may become confluent, appear in cycles, and involve thighs, buttocks, and lower abdomen. New lesions may be preceded by a burning or prickly sensation locally, and can be induced by prolonged standing, strenuous exercise, wearing tight garments, alcohol ingestion, or hot weather. Some patients have developed significant abdominal symptoms. 40 Examination of a biopsy specimen reveals either leukocytoclastic vasculitis or nonspecific purpura with mild lymphocytic perivasculitis in roughly equal frequency. In addition to the polyclonal hypergammaglobulinemia,

Figure 7. Benign hypergammaglobulinemic purpura of Waldenstriim. Small areas of macular hemorrhage.

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frequent and important laboratory associations include a positive rheumatoid factor, normal coagulation studies, an elevated erythrocyte sedimentation rate, and occasionally a positive antinuclear antibody determination and proteinuria. The significant rheumatoid factor present in this disease is an IgGanti-IgG complex, with a characteristic peak between 12S and 15S on analytic ultracentrifugation of serum. Detailed studies of this rheumatoid factor have shown that in up to two thirds of patients the anti-IgG factor is actually monoclonal. 18 Benign hyperglobulinemic purpura has been divided into primary and secondary forms. However, this is probably an arbitrary division. For instance, Kyle et al. 56 specifically selected their series of cases to include only those with primary forms of disease, but on follow-up half of the patients subsequently developed evidence of a connective tissue or lymphoproliferative disease. 56 In addition, there are at least four case reports of patients developing multiple myeloma 12 to 20 years after the diagnosis of hyperglobulinemic purpura was made. 10, 18 These reported cases, coupled with evidence of monoc!onal protein production in a very high percentage of patients, suggest that all patients with this syndrome may be at increased risk for developing keratoconjunctivitis sicca, Sj6gren's syndrome, lupus erythematosus, undifferentiated connective tissue disease, sarcoidosis, multiple myeloma, chronic lymphocytic leukemia, or other disorders. 10, 18, 40. 56 Alexander and Provost have noted an association between cutaneous vasculitis and anti-Ro (SSA) antibodies in a group of primary Sj6gren's syndrome patients. Six of these patients had a syndrome indistinguishable from Waldenstr6m's hyperglobulinemic purpura, and all were Ro antibody positive. It has been suggested that Ro antibody defines a subset of Sj6gren's patients who show evidence of vasculitis, hematologic abnormalities, and serologic hyperactivity.2 Other diseases significantly associated with an increased incidence of Ro antibody are systemic lupus erythematosus, especially subacute cutaneous lupus (SCLE), neonatal lupus syndrome, and homozygous C2 deficiency associated with a lupus-like syndrome and an SCLE-like cutaneous eruption. 2. 3 In this regard, 12 patients with discoid lupus erythematosus (DLE) and an associated dysgammaglobulinemia were recently reported. Eight of these patients had a monoclonal gammopathy, and four had either frank or "smoldering" myeloma. 74 Of interest is the fact that half of the patients were described as having generalized DLE, the original description given for the eruption in patients with SCLE and those with homozygous C2 deficiency with lupus eruptions. Moreover, there was a low incidence of the classic lupus band test on direct immunofluorescence of lesional skin, another finding more chqracteristic of SCLE than DLE.31 Finally, in 3 of the 12 patients either Sj6gren's syndrome or keratoconjunctivitis sicca was noted as an association. It would be interesting to know the incidence of Ro positivity in these patients. Certainly, it would be important in the future to study the overall incidence of Ro antibody positivity in patients with benign hypergammaglobulinemic purpura, as well as the incidence of occult monoclonal protein in Ro antibody-positive patients, regardless of the clinical setting, in an attempt to understand the significance of known associations between

170

WARREN W. PIETTE

Ro antibody positivity and certain lupus syndromes, Sjogren's syndrome, and vasculitis. LICHEN MYXEDEMATOSUS (PAPULAR MUCINOSIS) AND SCLEROMYXEDEMA

This disease group has been classified in various ways. The cutaneous clinical manifestations of lichen myxedematosus or papular mucinosis are discrete erythematous to yellowish papules that are lichenoid or conical in shape and are symmetrically distributed on the face, neck, and upper arms. These appear less frequently on the scalp, chest, and back. 21, 27. 68 In contrast, in scleromyxedema, the papules coalesce into plaques, especially on the face. Because of the coalescence of the papules, the clinical appearance may mimic that of acromegaly or generalized myxedema. Additionally, large areas of skin become brawny and indurated. These brawny plaques may be sufficient to interfere with function of the extremities, facial expressions, or opening the mouth. There are large deposits of mucin in the dermis, especially the upper dermis, as well as an increase in collagen and fibroblasts. On histologic examination of the diffuse thickened skin in scleromyx0dema the collagen bundles are found to be irregularly arranged, and there is extensive fib rob last proliferation in addition to the mucin deposition. The scleromyxedema group of patients are distinguished by the frequent but not invariable finding of an associated monoclonal gammopathy. In one series of 28 patients,26 nearly 80 per cent had a IgG monoclonal gammopathy, usually IgG h. When tested, 88 per cent of the monoclonal protein migrated in the slow gamma region of serum protein electrophoresis. This pattern is unusual in other series of monoclonal gammopathies or multiple myeloma; therefore, its presence is strongly suggestive of the diagnosis of scleromyxedema. Thus far, six cases of scleromyxedema with multiple myeloma have been reported,68 and one patient with scleromyxede ma-like lesions, monoclonal IgM, and angioimmunoblastic lymphadenopathy has also been reported. 77 It is remarkable that a slow gamma electrophoretic pattern is so frequently found, because these same proteins have been shown to be directed at different antigens. 92 Moreover, these patients have serum factors that stimulate fibroblast production of mucin in vitro,37 but this stimulant activity is not currently thought to be due to the paraprotein. In at least one instance, the paraprotein was found to be missing a fragment of the Fd portion. 46 , 68 A variety of therapeutic modalities have been used in scleromyxedema. Recent experience with alkylating cytotoxic agents has been promising but they should be used with prudence because of the known acute toxicity and the apparent long-term increase in secondary malignancies in other disorders that have been treated with alkylating agents. 21 , 27, 68 Resolution or regression of skin involvement following treatment with cytotoxic agents has occurred without any significant change in the amount of serum monoclonal protein, suggesting a mode of action independent of reduction in number of the monoclonal plasma cells. One report exists of successful treatment of scleromyxedema with etretinate (an aromatic retinoid) following a treatment failure with melphalan and prednisone.l 2

22,

,'1, "

Predominantly 19A

Predominantly 19G

Monoclonal IgA, IgG, 19.\\

Pyoderma gangrenosum 75

Acquired angioedema (some forms)4,51

Cutaneous T cell lymphoma, mycosis fungoides, Sezary syndrome l6 , ,", " \)[

Kaposi's sarcoma

Polyclonal 19A

Predominantly 19A

Predominantly IgA

IgG

GAMMOPATHY

ASSOCIATED

Yes

Yes

Yes

Yes

Yes

(IgA)

(IgA)

Yes

Yes

MYELOMA

ASSOCIATED

See article by "'lllggia and Lonberg

Erythematous papules, plaques and nodules, often with hyperkeratosis, Usually prominent epidermotropism oflvmphocytes on biopsy, Erythroderma with lymphocv(()sis of Sezary-type Iymphocytes

Angioedema

Painful ulcerations with violaceous undermined borders; often rapid enlargement, especially post debridement

Significant IgA deposition in dermal papillary tips in perilesional skin

excoriation.

Intensely pruritic vesicles on extensor surfaces, usually destroyed by

Flaccid, confluent pustules, especially on abdomen and in inguinal and axillary folds

Brownish red to violaceolls papules, plaques and nodules on extensor and periarticular surfaces, often tender, U suallv leukocvtoclastic vasculitis on biopsy' ,

1nduration of neck, shoulders, and truncal skin

PROMIKENT CCTANEOUS FEATURES

Sec article by M nggia and LOllherg

Systemic capillary leak s\'lldrolllP

Ulcerative colitis 15-20% Regional enteritis 5% MOlloclonal gamll10pathv 10%

50% idiopathic

Celiac disease Thyroid disease Malignancies, especially hitiocvtic lymphoma

Arthralgia

Antecedent acute infection Diabetes mellitus and angiopathy

ASSOCIATED SYSTE-"IlC FINDINGS

Cutaneous Diseases Associated with Monoclonal Gammopathy or Multiple Myeloma

Dermatitis herpetiformis"

"0

65, ""

Subcorneal pustular dermatitis 2s

Erythema e1evatum diutinum44,

Scleredema adultorum 1",

DISEASE

Table 1. r

.....

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Cfl ~

t"1

:t

U

..,

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172

WARREN W. PIETTE

OTHER CUTANEOUS DISEASES

Other cutaneous diseases may have important or intriguing associations with monoclonal gammopathy or multiple myeloma. Several such important associations are listed and briefly described in Table 1. It is very likely that with time the occurrence of other associations will be reported. For example, angioimmunoblastic lymphadenopathy (AILD) is another syndrome well known to be associated with both monoclonal and polyclonal gammopathies. Affected individuals commonly have a widespread erythematous papular eruption, and may on occasion have a nodular eruption. Histologic examination of such nodules may show features of immunoblast proliferation, arborization of dermal capillaries, and amorphous eosinophilic deposits considered characteristic of this disease. 81 Moreover, patients with AILD may have an increased incidence of Kaposi's sarcoma,47 a neoplasm that almost always presents in the skin and that is being seen more frequently today because of its occurrence in the acquired immune deficiency syndrome. Kaposi's sarcoma has also been associated with multiple myeloma, developing both before and after obvious symptoms of myeloma developed. The recognition of such cutaneous-systemic associations is important not only in the proper diagnosis and management of affected patients, but also, ultimately, in the understanding of the fundamental pathophysiologic processes leading to such recognized associations. REFERENCES 1. Alberts, D. S., and Lynch, P.: Cutaneous plasmacytoma in myeloma: relationship to tumor cell burden. Arch. Dermatol., 114:1784-1787, 1978. 2. Alexander, E. L., Arnett, F. C., Provost, T. T., et al.: Sjiigren's syndrome: association of anti-Ro (SS-A) antibodies with vasculitis, hematologic abnormalities, and serologic hyperreactivity. Ann. Intern. Med., 98:155-159, 1983. 3. Alexander, E. L., and Provost, T. T.: Cutaneous manifestations of primary Sjegren's syndrome: reflection of vaculitis and association with anti-Ro (SSA) antibodies. J. Invest. Dermatol., 80:386--391, 1983. 4. Atkinson, J. P., Waldmann, T. A., Stein, S. F., et al.: Systemic capillary leak syndrome and monoclonal IgG gammopathy: studies in a sixth patient and a review of the literature. Medicine, 56:225-239, 1977. 5. Bardwick, P. A., Zvaifler, N. J., Gill, G. N., et al.: Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome, report on two cases and a review of the literature. Medicine, 59:311-322, 1980. 6. Battaglini, J., and Olsen, T. G.: Disseminated xanthosiderohistiocytosis, a variant of xanthoma disseminatum, in a patient with a plasma cell dyscrasia. J. Am. Acad. Dermatol., 11 :750--755, 1984. 7. Beck, H., Andersen, J. A., Birkler, N. E., et al.: Giant basal cell carcinoma with metastasis and secondary amyloidosis: report of a case. Acta Derm. Venereol. (Stock.), 63:564-567, 1983. 8. Benson, M. D:, and Dwulet, F. E.: Prealbumin and retinol binding protein serum concentrations in the Indiana type hereditary amyloidosis. Arthritis Rheum., 26:14931498, 1983. 9. Braverman, 1. M.: Amyloidosis. In Skin Signs of Systemic Disease. 2nd ed. Philadelphia, W. B. Saunders Co., 1981, pp. 245-254. 10. Braverman, 1. M.: Multiple myeloma and the other dysproteinemias. In Skin Signs of Systemic Disease. 2nd ed. Philadelphia, W. B. Saunder Co., 1981, pp. 219--244.

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11. Breathnach, S. M., and Black, M. M.: Systemic amyloidosis and the skin: a review with special emphasis on clinical features and therapy. Clin. Exp. Dermato!', 4:517-536, 1979. 12. Brenner, S., and Yust, I.: Treatment of scleromyxedema with etretinate (letter). J. Am. Acad. Dermato!', 10:295-296, 1984. 13. Brownstein, M. H., and Helwig, E. B.: Systemic amyloidosis complicating dermatoses. Arch. Dermato!., 102: 1-7, 1970. 14. Brownstein, M. H., and Helwig, E. B.: The cutaneous amyloidoses. I. Localized forms. Arch. Dermato!', 102:8--19, 1970. 15. Brownstein, M. H., and Helwig, E. B.: The cutaneous amyloidoses. n. Systemic forms. Arch. Dermato!', 102:20--28, 1970. 16. Bryant, E., Ronan, S. C., and lossifides, I. A.: Plasma cell myeloma in a patient with a cutaneous T-celllymphoma. Cancer, 50:2122-2125, 1982. 17. Canlas, M. S., Dillon, M. L., and Loughrin, J. J.: Primary cutaneous plasmacytoma. Report of a case and review of the literature. Arch. Dermatol., 115:722-724, 1979. 18. Capra, J. D., Winchester, R. J., and Kunkel, H. C.: Hypergammaglobulinemic purpura. Studies on the unusual anti-l'-globulins characteristic of the sera of these patients. Medicine, 50:125-138, 1971. 19. Carrington, P. R, Sanus, I. D., Winder, P. R, et al.: Scleredema adultorum. Int. J. Dermato!. 23:514-522, 1984. 20. Cavo, M., Cobbi, M., Chetti, P., et al.: Secondary cutaneous plasmacytoma (letter). Acta Haemato!', 69:287-288, 1983. 21. Chanda, J. J.: Scleromyxedema. Cutis, 24:549--522, 1979. 22. Christy, W. C., Buckingham, R B., Barnes, E. L., et al.: Scleredema adultorum of Buschke: a clinical pathologic and cell culture study of two patients. J. Rheumato!., 10:595-601, 1983. 23. Codere, F., Lee, R D., and Anderson, R. L.: Necrobiotic xanthogranuloma of the eyelid. Arch. Ophthalmo!., 101 :60--63, 1983. 24. Cohen, A. S.: An update of clinical, pathologic, and biochemical aspects of amyloidosis. Int. J. Dermato!', 20:515-530, 1981. 25. Cream, J. J., Crimes, S. M., and Roberts, P. D.: Subcorneal pustulosis and IgA myelomatosis. Br. Med. J., 1:550, 1977. 26. Danby, F. W., Danby, C. W. E., and Pruzanski, W.: Papular mucinosis with IgC (K) M component. Can. Med. Assoc. J., 114:920-922, 1976. 27. Farmer, E. R, Hambrick, C. W., Jr., and Shulman, L. E.: Papular mucinosis: a clinicopathologic study offour patients. Arch. Dermato!', 118:9--13, 1982. 28. Fauci, A. S., Haynes, B. F., and Katz, P.: The spectrum of vasculitis: clinical, pathologic immunologic, and therapeutic consideration. Ann. Intern. Med., 89 (Part 1):660-676, 1978. 29. Flick, W. C., and Lawrence, F. R: Oral amyloidosis as initial symptom of multiple myeloma: a case report. Oral Surg., 49:18--20, 1980. 30. Furie, B., Voo, L., McAdam, K. P., et al.: Mechanism offactor X deficiency in systemic amyloidosis. N. Eng!. J. Med., 304:827-830, 1981. 31. Cilliam, J. N., and Sontheimer, R. D.: Distinctive cutaneous subsets in the spectrum of cutaneous lupus erythematosus. J. Am. Acad. Dermato!', 4:471-475, 1981. 32. Clenner, C. C.: AmylOid deposits and amyloidosis: the !3 fibrilloses. N. Eng!. J. Med., 302:1283--1292, 1333--1343, 1980. 33. Cogel, H. K., Searles, R P., Volpicelli, N. A., et al.: Primary amyloidosis presenting as Sj6gren's syndrome. Arch. Intern. Med., 143:2325-2326, 1983. 34. Comez, E. C., Margulies, M., Rywlin, A., et a!.: Cutaneous involvement by IgD myeloma. Arch. Dermato!', 114:1700-1703, 1979. 35. Coodman, D. S.: Plasma retinol-binding protein. In Sporn, M. B., Roberts, A. B., and Coodman, D. S. (eds.): The Retinoids. Vo!. 2. Orlando, Florida, Academic Press, 1984, pp. 41-88. 36. Greipp, P. R, Kyle, R. A., and Bowie, E. J. W.: Factor X deficiency in amyloidosis: a critical review. Am. J. Hemato!', 11:443-450, 1981. 37. Harper, R A., and Rispler, J.: Lichen myxedematous serum stimulates human skin fibroblast proliferation. Science, 199:545-547, 1978. 38. Hashimoto, K.: Progress on cutaneous amyloidosis (editorial). J. Invest. Dermato!', 82:13, 1984. 39. Hobbs, J. R, and Corbett, A. A.: Younger age of presentation and extraosseous tumor in

174

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IgD myelomatosis. Br. Med. J., 1:412-414, 1969. 40. Hudson, C. P., and Callen, J. P.: Cutaneous leukocytoclastic vasculitis with hyperglobulinemia and splenomegaly. A variant of hyperglobulinemic purpura of Waldenstrom. Arch. Dermatol., 120: 1224-1226, 1984. :l. Jancelwicz, Z., Takatsuki, K., Sugai, S., and Pruzanski, W.: IgD myeloma: review of 133 cases. Arch. Intern. Med., 135:87-93, 1975. 42. Jenkins, D., Lynde, C. W., and Stewart, W. D.: Histiocytic lymphoma occurring in a patient with dermatitis herpetiformis. J. Am. Acad. Dermatol., 9:252-256, 1983. 43. Katz, G. A., Peter, J. B., Pearson, C. M., et al.: The shoulder-pad sign-a diagnostic feature of amyloid arthropathy. N. Engl. J. Med., 288:34.h355, 1973. 44. Katz, S. 1.: Erythema elevatum diutinum. In Fitzpatrick, T. B., et al. (eds.): Update: Dermatology in General Medicine. New York, McGraw-Hill, 1983, pp. 20--27. 45. Kelly, J. J., Jr., Kyle, R. A., and Dyck, P. J.: Osteosclerotic myeloma and peripheral neuropathy. Neurology, 33:202-210, 1983. 46. Kitamura, W., Matsuoka, Y., Miyagawa, S., et al.: Immunochemical analysis of the monoclonal paraprotein in scleromyxedema. J. Invest. Dermatol., 70:305--308, 1978. 47. Kluin-Nelemans, H. C., Elbers, H. J., and Ramselaar, C. G.: Angioimmunoblastic lymphadenopathy followed by Kaposi's sarcoma. Arch. Dermatol., 120:958-959, 1984. 48. Knowling, M. A., Harwood, A. R, and Bergsagel, D. E.: Comparison of extramedullary plasmacytomas with solitary and multiple plasma cell tumors of bone. J. Clin. Oncol., 1 :255--262, 1983. 49. Kodama, J., Nakagawa, S., and Tanioku, K.: Plane xanthomatosis with antilipoprotein antibody. Arch. Dermatol., 105:722-727, 1972. 50. Kossard, S., and Winkelmann, R K.: Necrobiotic xanthogranuloma with paraproteinemia. J. Am. Acad. Dermatol., 3:257-270, 1980. 51. Kovary, P. M., Vakilzadeh, F., Macher, E., et al.: Monoclonal gammopathy in scleredema: observations in three cases. Arch. Dermatol., 117:536-539, 1981. 52. Kumakiri, M., and Hashimoto, K.: Histogenesis of primary localized cutaneous amyloidosis: sequential change of epidermal keratinocytes of amyloid via filamentous degeneration. J. Invest. Dermatol., 73:150--152, 1979. 53. Kumakiri, M., Sudoh, M., and Miuru, Y.: Xanthoma disseminatum. J. Am. Acad. Dermatol., 4:291-299, 1981. 54. Kyle, R. A.: "Benign monoclonal gammopathy": a misnomer? JAMA, 251:1849-1854, 1984. 55. Kyle, R. A., and Bayrd, E. D.: Amyloidosis: review of 236 cases. Medicine, 54:271-299, 1975. 56. Kyle, R. A., Gleich, G. J., Bayrd, E. D., et al.: Benign hypergammaglobulinemic purpura ofWaldenstrom. Medicine, 50:11~124, 1971. 57. Kyle, R A., and Greipp, P. R.: Amyloidosis (AL): clinical and laboratory features in 229 cases. Mayo Clin. Proc., 58:665--683, 1983. 58. Lever, W. F., and Schaumberg-Lever, G.: Cryoglobulinemia. In Histopathology of the Skin. 6th ed. Philadelphia, J. B. Lippincott Co., 1983, 170--171. 59. Libbey, C. A., Rubinow, A., Shirahana, T., et al.: Familial amyloid polyneuropathy. Demonstration of prealbumin in a kinship of German/English ancestry with onset in the seventh decade. Am. J. Med., 76:18-24, 1984. 60. Libbey, C. A., Skinner, M., and Cohen, A. S.: Use of abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis. Arch. Intern. Med., 143: 1549-1552, 1983. 61. Lynch, P. J., and Winkelmann, R K.: Generalized plane xanthoma and systemic disease. Arch. Dermatol., 93:639-646, 1966. 62. Maize, J. C., Ahmed, A. R., and Provost, T. T.: Xanthoma dissemination and multiple myeloma. Arch. Dermatol., 110:758-761, 1974. 63. McGrath, M. A., and Penny, R: Paraproteinemia: blood hyperviscosity and clinical manifestations. J. Clin. Invest., 58:1155--1162, 1976. 64. Mishkel, M. A., Cockshott, W. P., and Nazir, D. J.: Xanthoma disseminatum. Arch. Dermatol., 113:1094-1100, 1977. 65. Morrison, J. G. L., Hull, P. R., and Fourie, E.: Erythema elevatum diutinum, cryoglobulinemia, and fixed urticaria on cooling. Br. J. Dermatol., 97:99-104, 1977. 66. Moschella, S. L.: Plane xanthomatosis associated with myelomatosis. Arch. Dermatol., 101:68~687, 1970. 67. Muckle, T. J.: The "Muckle-Wells" syndrome. Br. J. Dermatol., 100:87-92, 1979.

MYELOMA, PARAPROTEINEMIAS, AND THE SKIN

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68. Muldrow, M. L., and Bailin, P. L.: Scleromyxedema associated with IgG lambda multiple myeloma. Cleve. Clin. Q., 50:189--195, 1983. 69. Muller, S. A., Sams, M., Jr., and Dobson, R. L.: Amyloidosis masquerading as epidermolysis bullosa acquisita. Arch. Dermatol., 99:739--797, 1969. 70. Nakanishi, T., Sobue, I., Toyokura, Y., et al.: The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology (Cleveland), 34:712-720, 1984. 71. Nassar, M. E.: Unusual physical sign of multiple myeloma. J. R. Soc. Med., 76:157-158, 1983. 72. Packman, C. H., and Leddy, J. P.: Cryopathic hemolytic syndromes. In Williams, W. J., et al. (eds.): Hematology. 3rd ed. New York, McGraw-Hill, 1983, pp. 641-647. 73. Pallares, R., Sancho, S., Nogues, R., et al.: Amyloidosis (AA type) associated with nodular nonsuppurative panniculitis. Ann. Intern. Med., 99:488-489, 1983. 74. Powell, F. c., Greipp, P. R., and Su, W. P.: Discoid lupus erythematosus and monoclonal gammopathy. Br. J. Dermatol., 109:355-360, 1983. 75. Powell, F. C., Schroeter, A. L., Su, W. P. D., et al.: Pyoderma gangrenosum and monoclonal gammopathy. Arch. Dermatol., 119:468-472, 1983. 76. Raflo, G. T., Farrell, T. A., and Sioussat, R. S.: Complete ophthalmoplegia secondary to amyloidosis associated with multiple myeloma. Am. J. Ophthalmol., 92:221-224, 1981. 77. Rahmani, R., Brenner, S., Krakowski, A., et al.: Angioimmunoblastic lymphadenopathy with scleromyxedema-Iike lesions and serum monoclonal protein. Isr. J. Med. Sci., 19:235-239, 1983. 78. Rubinow, A., and Cohen, A. S.: Skin involvement of generalized amyloidosis. A study of clinical involved and uninvolved skin in 50 patients with primary and secondary amyloidosis. Ann. Intern. Med., 88:781-785, 1978. 79. Rubinow, A., and Cohen, A. S.: Skin involvement in familial amyloidotic polyneuropathy. Neurology, 31:1341-1345, 1981. 80. Russell Jones, R.: The cutaneous manifestations of paraproteinemia. Part I. Br. J. Dermatol., 103:335-344, 1980. 81. Russell Jones, R.: Cutaneous manifestations ofparaproteinemia. Part n. Br. J. Dermatol., 104:209--220, 1981. 82. Saraiva, M. J. M., Costa, P. R., and Goodman, D. S.: Studies on plasma transthyretin (prealbumin) in familial amyloidotic polyneuropathy, Portuguese type. J. Lab. Clin. Med., 102:590--603, 1983. 83. Shah, A., Klimo, P., and Worth, A.: Multiple myeloma first observed as multiple cutaneous plasmacytomas. Arch. Dermatol., 118:922-924, 1982. 84. Simon, B. G., and Moutsopoulos, H. M.: Primary amyloidosis resembling sicca syndrome. Arthritis Rheum., 22:932-934, 1979. 85. Stankler, L., and Davidson, J. F.: Multiple extramedullary plasmacytomas of the skin: case report with a note on prognosis. Br. J. Dermatol., 90:217-221, 1974. 86. Stenkvist, B., Westermark, P., and Wibel!, L.: Simple method of diagnostic screening for amyloidosis. Ann. Rheum. Dis., 33:75-76, 1974. 87. Venencie, P. Y., Powel!, F. c., Su, W. P. D., et al.: Scleredema: a review of thirty-three cases. J. Am. Acad. Dermatol., 11:128--134, 1984. 88. Venencie, P. Y., Winkelmann, R. K., Friedman, S. J., et al.: Monoclonal gammopathy and mycosis fungoides. Report of four cases and review of the literature. J. Am. Acad. Dermatol., 11 :576-579, 1984. 89. Venencie, P. Y., Winkelmann, R. K., Puissant, A., et al.: Monoclonal gammopathy in Sezary syndrome. Report of three cases and review of the literature. Arch. Dermatol., 120:605-608, 1984. 90. Wallach, D., Cottentot, F., Pelbois, G., et al.: Subcorneal pustular dermatosis and monoclonal IgA. Br. J. Dermatol., 107:229--234, 1982. 91. Weiss, V. C., Barsky, G. J., and Solomon, L. M.: Cutaneous T-Iymphocyte lymphoma in association with multiple myeloma. Arch. Dermatol., 120:499--501, 1984. 92. Wells, J. V., Fudenberg, H. H., and Epstein, W. L.: Idiotypic determinants on the monoclonal immunoglobulins associated with papular mucinosis. J. Immunol., 108:977983, 1972. 93. Whitaker, J. N., Hashimoto, K., and Quinones, M.: Skeletal muscle pseudohypertrophy in primary amyloidosis. Neurology, 27:47-54, 1977. 94. Wiltshaw, E.: The natural history of extramedullary plasmacytoma and its relation to solitary myeloma of bone and myelomatosis. Medicine, 55:217-238, 1976.

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95. Winer, R. L., Wuerker, R. B., Erickson, J. 0., et al.: Ultrastructural examination of urinary sediment: value in renal amyloidosis. Am. J. Clin. Pathol., 71:36-39, 1979. 96. Wuepper, K. D., and MacKenzie, M. R.: Cutaneous extramedullary plasmacytomas. Arch. Dermatol., 100:155-164, 1969. 97. Zilko, P. J., and Dawkins, R. L.: Amyloidosis associated with dermatomyositis and features of multiple myeloma. The progression of amyloidosis associated with corticosteroid and cytotoxic drug therapy. Am. J. Med., 59:448-452, 1975. Department of Dermatology The University ofIowa Hospitals and Clinics Iowa City, Iowa 52242