1231

Crystalglobulinemia Syndrome A Manifestation of Multiple Myeloma

Nigel J. Ball, M.B.,* Wayne Wickert, M.D.,t Lennavf H. Man, M.D., F.R.C.P.C.,$ and Johrz F. Thaell, M.D., F.R.C.P.C., F.A.C.P.t

Background. Crystalglobulinemia syndrome (CS) is a rare vasculopathy that may arise as a complication of multiple myeloma (MM).

Methods and Results. A patient with multiple my- eloma in whom crystalglobulinemia syndrome was the initial manifestation with polyarthralgias, cutaneous ul- ceration, and lower limb ischemia requiring bilateral amputations is reported.

Conclusion. The rare syndrome of crystalglobuline- mia may be associated with multiple myeloma, so it is important that clinicians be aware of this syndrome and its clinical and morphologic features. Cancer 1993; 71: 1231-4.

Key words: crystalglobulinemia, multiple myeloma, vas- culitis, monoclonal gammopathy.

Crystalglobulinemia syndrome (CS) usually occurs as a paraneoplastic syndrome associated with multiple my- eloma (MM).',2 It is a rare condition; only 34 patients have been reported previ~usly. '-~ The demographics of CS are similar to those of MM.* It occurs more often in male patients (ma1e:female ratio, 2.4:1), at a median age of 55 years (range, 26-82 years).'-7 The syndrome may be the initial manifestation of underlying MM and typi- cally presents as a systemic necrotizing vasculitis with rapidly progressive renal failure, polyarthropathy, pe- ripheral neuropathy and cutaneous ulcerations, pete- chiae, and ecchymoses.'f2 The underlying mechanism of vascular injury is an immunoglobulin G (IgG)2 or occasionally light chain' paraprotein that spontane-

From the Departments of *Pathology and tMedicine, University of Calgary, Foothills Hospital, Calgary General Hospital, Tom Baker Cancer Centre and $Associated Clinical Laboratories, Calgary, Al- berta, Canada.

The authors thank Dr. A. Chang, Calgary General Hospital and Dr. J. Wootliff, Calgary District Hospital Group, for photographic assistance.

Address for reprints: John F. Thaell, M.D., F.R.C.P.C., F.A.C.P., 204, 803-1st Avenue, NE, Calgary, Alberta T2E 7C5, Canada.

Accepted for publication August 4, 1992.

ously crystallizes in the microvasculature, where there is relative stasis or cooling. Intravascular crystals dam- age the vascular endothelium, which initiates the coagu- lation cascade to produce thrombosis and local isch- emia.' A patient with MM presenting as CS secondary to an IgG kappa monoclonal gammopathy and requir- ing bilateral below knee amputations is reported.

Case Report

A 55-year-old man went to his family physician with po- lyarthralgias in both knees and the metacarpalphalangeal and interphalangeal joints of both hands and feet. Two months earlier, anterior uveitis of the right eye was diagnosed and treated with prednisone 25 nig daily. The patient had tender, warm swollen wrists and interphalangeal joints. Circulating rheumatoid factor, antinuclcar antibodies, Cg, C,, immune complexes and hepatitis B serologic results were normal. He was treated symptomatically with nonsteroidal anti-inflam- matory agents.

Three months later he had a purpuric rash of the lower legs. He was hypertensive (180/110 mm Hg) with 3+ pro- teinuria and serum urea of 15.8 mmol/l, creatinine of 235 pmol/l, and creatinine clearance of 0.49 ml/second. Total serum protein was 67 g/l; albumin was 22 g/l. Serum protein electrophoresis revealed an IgG kappa monoclonal gammo- pathy with serum immunoglobulin concentration of 22.5 g/l IgC (normal, 6-13 g/l), 0.13 g/1 IgA (normal, 0.7-3.12 g/l), and 0.26 g/IlgM (normal, 0.56-3.52 g/l). Immunoelectropho- resis of urine identified free kappa light chains, but RO crystal- luria. The bone marrow was abnormally hypercellular with more than 50% infiltration of atypical plasma cells. Results of a skeletal survey were normal. Skin biopsy demonstrated a superficial perivascular lymphoplasmacytic dermal infiltrate. Hemoglobin was 93 g/1, leukocyte count was 8.6 X 109/1, and the platelet count was 170 X lo9/]. Serum calcium, electro- lytes, and liver function tests were normal. A diagnosis of multiple myeloma was made, and the patient was treated with melphalan 6 mg and prednisone 60 mg daily for 7 days. Nifedipine 10 mg three times daily was added for control of hypertension.

One month after the diagnosis was made, the patient had a rash that extended proximally to involve the buttocks and purpuric lesions of the feet had ulcerated (Fig. 1). Pain from

1232 CANCER February 25, 2993, Volume 71, No. 4

Figure 1. Ulcerated purpuric lesions on the right foot.

persistent arthralgias and enlarging lower limb ulcers severely limited his mobility. Serum urate was 0.4 mmol/l (normal); cryoglobulins and cryofibrinogen were not detected. A repeat cutaneous biopsy showed an ulcer lined by inflammatory de- bris containing pale eosinophilic, refractile, birefringent, hexa- gonol, rhomboidal, and rectangular crystals between 130 and 20 pm in maximal dimension. Similar crystals in the adjacent dermal capillaries impinged on endothelial surfaces with thrombosis and entrapment of red blood cells (Fig. 2). An active vasculitis was not present, and a Congo red stain for amyloid was negative. Immunoperoxidase staining of the paraffin-embedded tissue with rabbit polyclonal antibodies to the heavy chain portion of human IgG, A, M, D, kappa and lambda light chains using a peroxidase-antiperoxidase tech- nique stained these crystals with 1gG and kappa. A portion of the biopsy was transported in Michel solution, washed with Michel buffer, and frozen for cutaneous immunofluores- cence. There was no immunofluorescent staining with poly- clonal rabbit antibodies to the heavy chain portion of human

IgG, A, M, C,, or kappa and lambda light chains. Fibrin was deposited in thrombosed capillaries and diffusely around the ulcer base (fluorescein-conjugated plasma protein antisera). A section stained with hematoxylin and eosin showed empty quadrilateral-shape spaces in and around blood vessels but no crystalline deposits. Subcutaneous abdominal fat aspira- tion for amyloid was negative. A diagnosis of crystalglobulin- emia syndrome was made, and the patient was treated with cyclophosphamide 150 mg daily in place of melphalan, and admitted to hospital for three courses of plasmapheresis.

After plasmapheresis, his serum IgG fell to normal (13 g/l) and serum creatinine to 189 pmol/, with a creatinine clearance of 0.74 ml/second. Ophthalmologic examination revealed a corneal marginal dystrophy with paralimbic crys- talline deposits. While the patient was in the hospital, cutane- ous ulcers on the feet enlarged and extended to bone, which required surgical debridement and amputation of the right fifth toe. Despite the debridement, nonhealing ulcers per- sisted 6 weeks after surgery, and the patient remained immo- bile. Bilateral below-knee amputations were performed. Histo- logic examination of the legs identified features similar to those found at the cutaneous biopsy. In addition, crystalglobu- lins occluded medium-size arteries in the subcutaneous fat and skeletal muscle (Fig. 3).

One month later, lower limb prostheses were fitted for the patient, and he was discharged from the hospital using crutches, 3 months after being admitted to the hospital for plasmapheresis. Eleven months after the diagnosis, the pa- tient's multiple myeloma and crystalglobulinemia remain in clinical remission. He continues to receive maintenance ther- apy with oral cyclophosphamide.

Discussion

This patient had features typical of CS as a systemic vasculopathy with polyarthralgias and cutaneous ulcer-

Figure 2. The second cutaneous biopsy showing epidermal necrosis and crystalglobulins filling dermal capillaries (H & E, original magnification XlOO).

Crystalglobulinemia Syndrome/Ball e t al. 1233

Figure 3. Left below-knee amputation specimen with crystalglobulins occluding a recanalized artery (H & E, original magnification X200).

ation associated with MM. Although CS usually is asso- ciated with MM at the time of diagnosis, in 26% of patients, it occurs as essential crystalglobulinemia un- associated with a lymphoreticular malignan~y.’-~ In these patients, MM has not developed in a follow-up period of 3-20 years from diagnosis (median, 7.75 year^),',^-^,^ suggesting that essential crystalglobuline- mia is a separate disease that will not evolve into MM in most patients. CS also is distinct from the asymptomatic spontaneous formation of crystals in “in vitro” blood samples, which has been reported in association with MM, Waldenstrom macroglobulinemia,’O and hairy cell leukemia.” Spurious leukocytosis caused by the count- ing of crystals as leukocytes by automated blood ana- lyzers may ~ c c u r . ~ ” ~ The mechanism of crystal forma- tion is similar to that of CS and essential crystalglobu- linemia, for which crystallization occurs secondary to interactions between IgG paraproteins, either between their Fc fragments” or with albumin,6 aggravated by local cooling and stasis in the microvasculature or in vitro. In patients with MM without CS, tissue deposi- tion of crystalline paraproteins is reported, although in these patients the reason for the absence of clinical manifestations and the mechanism of crystal formation have not been e l~c ida ted . ’~~’~

Negative immunofluorescence in biopsy specimens from patients with CS has been reported p r e v i ~ u s l y . ~ , ~ , ~ Two explanations of this phenomenon have been pro- posed. The first is that antigenic binding sites on IgG paraproteins may be masked or altered.3 Alternatively, and more plausibly, removal of IgG during the washing procedure before the application of fluorescent anti- sera5 could explain the negative immunofluorescent

findings. The last explanation seems most likely be- cause crystalglobulins were not seen in the routinely stained sections processed for immunofluorescence, and crystalglobulins are known to be water ~ o l u b l e . ~ This hypothesis is supported by the characteristic ap- pearance of the paraprotein crystals on section^',^ stained with hematoxylin and eosin and their reaction with antibodies to IgG and kappa in the paraffin-em- bedded tissue.

In patients previously reported, CS has been treated with plasmapheresis to reduce crystalglobulins, steroids, and chemotherapy for the underlying MM, and supportive measures, including hemodialysis. Al- though this has met with only varied succes~‘~~” the secret to successful management appears to be early recognition and d iagno~is .~ In the patient reported here, circulating paraproteins were reduced, but it was too late to reverse the patient’s obstructive vasculopathy with arterial occlusion, so bilateral below-knee ampu- tations were required. Only one previously reported pa- tient required amputation, and that patient had essen- tial crystalglobulinemia caused by lambda light chain paraproteinemia.’ Most severe cases of CS have been complicated by acute renal failure.’ Our patient also is unique because of the absence of overt renal symptoms and crystalluria, perhaps because the warmer tempera- ture in the renal vasculature, compared with the periph- eral vasculature, prevented crystallization of this para- protein. ’

Most of the data on CS have been based on individ- ual case reports. Nevertheless, there appears to be a strong association between CS and MM, so it is impor- tant for practicing physicians to be aware of this syn-

1234 CANCER February 25, 2993, Volume 71, No. 4

drome because it may be the first indication of an un- derlying MM.'-7 In patients with systemic obstructive vasculopathy, clinical suspicion should be high and perhaps prompt screening with serum protein electro- phoresis. An aggressive approach to the diagnosis of CS and MM may enable patients to have diagnoses at an earlier stage, when survival rates are better.')l5 Only through the increased awareness of CS will its true inci- dence and relevance to the diagnosis and course of MM be established.

References

1. Stone GC, Wall BA, Oppliger IR, Wener MH, Jolly SL, Aquirre A et al. A vasculopathy with deposition of lambda light chain crys- tals. A n n Intern Med 1989; 110:275-8.

2. Dotten DA, Pruzanski W, Olin J, Brown TC. Crystalglobuline- mia. Can Med Assoc 1976; 114:909-12.

3. Mullen B, Chalvardjian A. Crystalline tissue deposits in a case of multiple myeloma. Arch Pathol Lab Med 1981; 105:94-7.

4. Langlands DR, Dawkins RJ, Matz LR, Cobain TJ, Goatcher 1', Papadimitrious JM, et al. Arthritis associated with crystallizing cryoprecipitable IgG paraprotein. A m J Med 1980; 68:461-5.

5. Grossman J, Abraham GN, Leddy JP, Condemi JL. Crystalglobu- linemia. A n n Intern Med 1972; 77:395-400.

6. Mills LE, Brettman LR, Jentoft JE, Viner ED. Crystallocryoglobu- linemia resulting from human monoclonal antibodies to albu- min. A n n Intern Med 1983; 99:601-4.

7. Cummings FJ, Park CH, Bogaars HA, Kalderon AE, Melnicoff 1, Kaplan SR, et al. Successful therapy of crystalcryoglobulinemia: a case report. Med Pediatr Otrcol 1979; 7:181-90.

8. Conklin R, Alexanian R. Clinical classification of plasma cell myeloma. Arch Intern Med 1975; 135:139-52.

9. Taft EG, Grossman J, Abraham GN, Leddy JI', Lichtman MA. Pseudoleukocytosis due to cryoprotein crystals. A m J Clin Pathol

10. Dalgaard EB. A case of hyper- and macroglobulinemia accompa- nied by atypical lymphatic hyperplasia. Acta Pathol Microbiol Scand 1950; 27:506-12.

11. Krause JR. Nitiyanant P, Rabin BS. Crystalglobulinemia in hairy cell leukemia. Cancer 1978; 42:2798-801.

12. Abraham GN, Leddy JP, Grossman J, Condemi JJ. Properties of crystalline IgG3 globulin. Biochem Biophys Res Commun 1972;

13. Truong LD, Mawad J, Cagle P, Mattioli C. Cytoplasmic crystals in multiple myeloma associated Farconi's syndrome. Arch Pathol Lab Med 1989; 113:781-5. Hirota S, Migamoto M, Kasugait, Kitamura Y, Morimwa Y. Crystalline light-chain deposition and amyloidosis in the thy- roid gland and kidneys of a patient with myeloma. Arch Pathol Lab Med 1990; 114:429-31.

15. Finnish Leukaemia Group. Improved long-term survival in mul- tiple myeloma. Eur J Haematol 1989; 43:385-8.

1973; 60~669-74.

461162-6.

14.