Von Willebrand factor antigen levels in Kaposi's sarcoma

Ill

I I

II

I

Ill

I

I Illl

I

lUl

Von Willebrand factor antigen levels in Kaposi's sarcoma Neal S. Penneys, M.D., Ph.D.,* Recia Kott-Blumenkranz, M.D. ,* Frank Civantos, M.D. ,** and Jessie Kent, M.T. (ASCP)** Miami, FL Consistent elevations of plasma yon Willebrand factor antigen were observed in otherwise healthy elderly patients with Kaposi's sarcoma. The elevations were predominantly of the endothelial cell-derived antigen, as opposed to the factor VIII procoagulant, with resultant elevations in the antigen/procoagulant ratios. Lesser elevations were seen in a group of age-matched control subjects who did not have Kaposi's sarcoma or intercurrent illness. The greater elevations in plasma von Willebrand factor antigen therefore appear to be the direct consequence of the presence of Kaposi's sarcoma cells. Our findings also suggest that there is a direct relationship between tumor load and degree of yon Willebrand factor antigen elevation. (J AM ACAD DERMATOL 15:1214-1217, 1986.)

The von Willebrand factor is a high-molecularweight carrier molecule with antigenic properties that are recognized by heterologous antibodies. The von Willebrand factor antigen may be measured by electroimmunoassay in plasma. Although the von Willebrand factor antigen is present in megakaryocytes, platelets, and endothelial cells, the plasma levels are maintained by endothelial cells that release von Willebrand factor antigen into the plasma.l Platelets have surface receptors that attach to the plasma von Willebrand factor antigen, which function then as a glue, facilitating platelet attachment to injured vessel walls. Another function of the von Willebrand factor antigen is to act as a carrier protein that complexes with low-molecular-weight clotting factor VIII procoagulant produced by hepatocytes and possibly other cells. From the Departments of Dermatology* and Pathology,** University of Miami School of Medicine. Accepted for publication June 27, 1986. Reprint requests to: Dr. Neal S. Penneys, Box 016940, Miami, FL 33101.

1214

Levels of factor VIII procoagulant can be determined in plasma by clotting assays. Normally the proportion of yon Willebrand factor antigen measured by electroimmunoassay to factor VIII procoagulant determined by clotting assay is a 1 : 1 ratio. The presence of yon Willebrand factor antigen (previously known as factor VIII-related antigen), as well as of blood group antigens within the spindle cells and vascular aggregates of Kaposi's sarcoma, supports the endothelial derivation of this tumor) With the understanding that the lesions in Kaposi's sarcoma are composed of a proliferating cell type with a distinctive antigenic marker (yon Willebrand factor antigen), we have investigated the possibility of plasma elevations of the antigen in patients with this neoplasm. Tumor-derived antigen elevations would have to be distinguished from the nonspecific elevations of the factor VIII complex (von WiUebrand factor antigen and factor VIII procoagulant) as an acute-phase reactant. In patients with acquired immunodeficiency syndrome-related Kaposi's sarcoma, the associated opportunistic infections would cause acute,

Volume 15 Number 6 December, 1986

Von Willebrand factor antigen levels in Kaposi's sarcoma

1215

Table I. Elderly (non-acquired immune deficiency syndrome) Kaposi's sarcoma Patient age (yr), sex

69, 60, 77, 83, 80, 82, 86, 91, 62,

M M M M M M M M M

80, M 77, F

F VIII Ag/C vWF: Ag

F VKI: C

ratio

Extent of disease

Duration of disease (yr)

211 257* 255 137 516" 365 190 289* 356

200 135' 96 108 227* 185 132 207* 190

1:1 1:9 2:7 1:3 2:3 2:0 1: 4 1:4 1:9

Minimal Minimal Minimal Minimal Extensive Minimal Minimal Moderate Moderate

11/2 3 11/2 1 5 Unknown 7 1 1

940 175

200 78

4:7 2:2

Extensive Minimal

15 Unknown

Treatment

None None None Curettage Radiationt None Curettage Radiationt Radiation, chemotherapy Radiation None

F VIII Ag/C ratio: Factor VIII antigen/procoagulant ratio; F VIII:C: factor VIII procoagulant; vWF:Ag: yon Willebrand factor antigen. *Average of multiple determinations. tTherapy ongoing,

phase reactant increases in yon Willebrand factor antigen and factor VIII procoagulant. The current study was undertaken with elderly patients who had Kaposi's sarcoma but not acquired immunodeficiency syndrome in order to eliminate the nonspecific elevations that are attributable to intercurrent illness. MATERIAL AND METHODS Blood samples were collected from ten adult male patients ranging in age from 62 to 91 years old and from one 77-year-old female patient with biopsy-proved cutaneous Kaposi's sarcoma. Three of the patients who were receiving ongoing therapy had serial factor VIII complex determinations. Two of these patients were receiving radiation therapy and the third, chemotherapy. None of the patients had documented extracutaneous involvement. All had predominant involvement of the lower extremities, ranging in degree from scattered papules in patients with minimal disease to discrete and confluent plaques and tumors on the legs and lower part of the trunk in the two patients with extensive disease. Factor VIII procoagulant in plasma was measured by clotting assay using commercially available activated partial thromboplastin time (APTT) reagent~ (General Diagnostics, Morris Plains, NJ). Plasma levels of yon Willebrand factor antigen were determined by electroimmunoassay using Calbiochem-Behring (La Jolla, CA) antiserum? The concentration of yon Willebrand

factor antigen is expressed as a percentage of the normal expected values, with normal ranging from 70% to 150%. The ratio of yon Willebrand factor antigen to factor VIII procoagulant is calculated directly, with the normal value being 1. A group of matched older patients with other skirt tumors (basal cell carcinoma, squamous cell carcinoma, seborrheic keratoses, and nevi) was used to ascertain the control values of von Willebrand factor antigen and factor VIII procoagulant. RESULTS Ten of eleven patients were found to have elevations in von Willebrand factor antigen levels, with a mean antigen level of 362% (Table I). Nine of these patients demonstrated an elevation in the antigen/procoagulant ratio as well (mean = 2.1). One patient was remarkable for the extreme elevation in both antigen and ratio, perhaps c0rrelating with the extent and duration of the disease. When this patient's values were excluded, the mean antigen level was 286 and the mean ratio, 1.8. Despite an obviously small sample size, there does appear to be a rough correlation between the extent of disease as judged visually and the degree of antigen elevation (Fig. 1). Those patients tested sequentially while undergoing therapy had persistent elevations in their antigen levels and ratios, as well as persistent clinical disease. Age-matched

1216

Journal of the American Academy of Dermatology

Penneys et al

900 800 700 600

i1: I H

r.1 .c

500

400

//

300

MODERATE

MINIMAL

EXTENSIVE

EXTENT OF L~TSEASE

Fig. 1. Correlation between the extent of Kaposi's sarcoma as assessed visually and plasma von Willebrand factor antigen levels. control patients with other cutaneous neoplasms showed values of factor VIII procoagulant ranging from 71 to 146 and values of von Willebrand factor antigen between 100 and 208, with an antigen/ procoagulant ratio of 1.3:1. DISCUSSION

The yon Willebrand factor antigen is a known marker of endothelial cells. The determination of plasma yon Willebrand factor antigen levels is standard in hematology laboratories in the diagnosis of conditions such as hemophilia A and von Willebrand's disease. Using this testing method, we have found consistent elevations in plasma yon Willebrand factor antigen levels in otherwise healthy elderly men with cutaneous Kaposi's sarcoma. More significantly, the elevations were predominantly of the endothelial cell-derived antigen, as opposed to factor VIII procoagulant, with resultant elevations in the antigen/procoagulant ratios. Elevations in plasma yon Willebrand factor antigen therefore appear to be the direct consequence of the presence of Kaposi's sarcoma cells. This finding is notable because of the limited extent of disease in most of our patients. Our findings do suggest, as well, that there is a distinct relationship between tumor load and degree of von Willebrand factor antigen elevation. This relation-

ship between tumor load and plasma von Willebrand factor antigen levels is not unique; for example, there is such a relationship between colorectal carcinoma and levels of carcinoembryonic antigen. The von Willebrand factor antigen is a known acute-phase reactant with elevated levels in patients with diabetes, heart failure, infections, and neoplasms. 4 In particular, cytomegalovirus infection affecting endothelial cells in patients with acquired immunodeficiency syndrome can result in massive elevations of the von Willebrand factor antigen. The extent of non-Kaposi's neoplastic and infectious illness must therefore be taken into account when antigen levels are interpreted in patients with acquired immunodeficiency syndrome. In patients with Kaposi's sarcoma of the classic type, alterations in von Willebrand factor antigen levels and antigen/procoagulant ratios may prove to be useful markers with regard to cutaneous and systemic dissemination and therapeutic efficacy as long as the patient does not have concomitant infections or other illnesses. REFERENCES 1. Jaffe EA: Endothelialcells and the biologyof factor VIII, N Engl J Mcd 296:377-383, 1977. 2. NadjiM, MoralesAR, Ziegels-WeissmanJ, Penneys NS:

Volume 15 Number 6 December, 1986

Von WiUebrand factor antigen levels in Kaposi' s sarcoma

Kaposi's sarcoma: Immunohistochernicalevidencefor an endothelial origin. Arch Pathol Lab Med 105:274-275, 1981. 3. Miale JB: Laboratory medicine: Hematology, ed. 6. St. Louis, 1982, The C. V. Mosby Co., pp. 929-932.

II

II II

I

4. Ratnoff OD: The role of haemostatic mechanisms. Clin Haematol 10:261-281, 1981.

I

II I

Histopathologic studies in S6zary syndrome and erythrodermic mycosis fungoides: A comparison with benign forms of erythroderma Henry J. Sentis, M.D., Rein Willemze, M . D . , * and Erik Scheffer, M.D.**

Leiden and Amsterdam, The Netherlands Histologic sections from eleven patients with S6zary syndrome were reviewed and compared with those of four patients with erythrodermic mycosis fungoides and twenty-four patients with a benign form of erythroderma, including fifteen patients with chronic dermatitis, four with a generalized drug eruption, and five with an erythrodermic psoriasis. The most important discriminating histologic feature in patients with S6zary syndrome was the presence of a monotonous bandlike or perivascular infiltrate in the papillary dermis, mainly composed of large cerebriform-m0nonuclear cells, as seen in seven of eleven S6zary syndrome patients. Pautrier's microabscesses were observed in seven of eleven S6zary syndrome patients, two of four patients with erythrodermic mycosis fungoides, but not in any of the patients with a benign form of erythroderma; their presence was therefore considered a reliable criterion in differentiating erythrodermic cutaneous T cell lymphoma from benign forms of erythroderma. However, features of chronic dermatitis were often found superimposed on those of S6zary syndrome and were even predominating in four of eleven S6zary syndrome patients. Moreover, four patients with a benign form of erythroderma showed a histologic picture suggestive of cutaneous T cell lymphoma. Therefore, in dubious cases repeated skin biopsies, additional investigations of lymph nodes and peripheral blood, and careful follow-up are mandatory for the achievement of a correct diagnosis. (J AM ACAD DERMATOL15:1217-1226, 1986.)

From the Departments of Dermatologyand Pathology, University Hospital, Leiden,** and the Department of Dermatology,Free University, Amsterdam.* Accepted for publicationJune 27, t986. Reprint requests to: Dr. H. J. Sentis, Departmentof Dermatology, UniversityHospital,P.O. Box 9606, 2300 RC Leiden,The Netherlands.

S6zary syndrome is a cutaneous T cell lymphoma characterized by an exfoliative or infiltrated erythroderma with severe pruritus, lymphadenopathy, and atypical !ymphocytes (S6zary cells) in the peripheral blood, l,z Differentiation between S6zary syndrome and erythroderma on the basis 1217