Circulating Immune Complexes in Malignant Melanoma: Serial Studies in 130 Patients

Abstract

We evaluated the ability of repeated measurements of circulating immune complexes (CIC) to predict for tumor recurrence in 130 patients with malignant melanoma. Twenty-two patients had level 2, 45 had level 3, and 51 had level 4/5, stage I disease in remission at the start of monitoring, while 12 had stage II disease. The polyethylene glycol precipitation assay was used for serial studies, based on an initial comparative evaluation with the Clq-binding and Raji assays. The study averaged 22 ± 11 months (6–43 months) and an average of 22 ± 5.3 assays were performed per patient (range 3–36), with a follow-up of 4 years. CIC were present in sera in recurrent, irregular ‘bursts’ of activity. Serial measurements doubled the incidence of CIC compared to single determinations. Only 23% of these bursts of activity were clearly related temporarily to documented recurrences, while 34% occurred with treatment events such as surgery or immunotherapy, and 42% occurred without correlation to either recurrence or treatment. CIC activity was greater and more closely related to recurrence in high-risk stage I (level 4,5) and stage II patients. Whether analyzed as positive sera or as bursts of elevated CIC activity, CIC assays predicted for recurrence at the 5% significance level. The assay was highly sensitive (97%), but with poor specificity (21%) with many false positives (79%). The assay was helpful at ruling out recurrences (95%), but poor at ruling them in (29%). The advantage was seen only in high-risk stage I and II patients, and there was no advantage to serial assays over random single determinations. Although generally, CIC in the sera of melanoma patients were found to predict for recurrence, the use of serial CIC measures monitoring of individual patients cannot be recommended.

Prognostic value of serial determinations of circulating immune complex levels in malignant melanoma

“…In previous serial studies, recurrence/progressive growth of malignant melanoma was reported to be associated with significant changes in clC levels [15], with raised clC levels [3,15,16], or with reduced clC levels [14]. In contrast to these findings, significant changes in clC and C3d levels, defined by reference to the changes that occurred in serial samples from healthy controls, were not associated with the development of recurrent disease in our 50 patients with malignant melanoma.…”

“…The usefulness of serial measurements of clC to predict recurrence of disease should, if possible, be evaluated in patients without known systemic dissemination of disease as in the presented study and in the studies of Bharwani et al [3], Ronai et al [14], and Ruell et al [16]. In the study of Rossen et al [15], 35 of the 53 melanoma patients had distant metastases when entering the study, and the conclusions therefore rely rather on progression than recurrence.…”

“…Therapeutic manipulations such as surgery, chemotherapy, and immunotherapy may influence the cIC levels [3,10,16,17,19]. Several patients included in the previously mentioned serial studies of malignant melanoma were tested while undergoing treatment (combinations of surgery, chemotherapy, and immunotherapy).…”

“…These solid-phase Clq assays have the advantage over the fluid-phase Clq tests used by Rossen et al [15] and Ruell et al [16] in that they are specific for immunoglobulin and more sensitive [18]. The lack of specificity for cIC is also a major problem in the polyethylene glycol precipitation methods used by Bharwani et al [3] and Ronai et al [14], as well as in the nephelometric monoclonal rheumatoid factor assay of Ruell et al [16]. In the present study, the dose-response curves obtained with AHG (data not shown) and the high cIC levels found in the SLE control sera (Table 1) proved the efficacy of the IC assays.…”

“…Only few serial studies have been conducted in patients with malignant melanoma. The results are contradictory, since recurrence/progressive Offprint requests to: Anne Bukh, Department of Immunology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada growth of malignant melanoma has been associated with the occurrence of raised clC levels [3,15,16] as well as reduced clC levels [14]. Moreover, the varying number of false-positive and false-negative results in these studies warrants consideration.…”