- Email: [email protected]
Cellular hypersensitivity in patients with adenomatous hyperplasia and adenocarcinoma of the endometrium
Cellular hypersensitivity in patients with adenomatous hyperplasia and adenocarcinoma of the endometrium SIDNEY
Y.
CARMEL
J.
DAVID
CHEN,
M.D.
COHEN,
M.D.
KOFFLER,
M.D.
New York, New York Cellular hypersensitivity was studied in patients with adenomatous hyperplasia and adenocarcinom.a of the endometrium with the use of dinitrochlorobenzene (DNCB) skzn tests and inhibition of leukocyte migration by homologous and autologous tumor antigen. Inhibition of leukocyte migration by homologous endometrial carcinoma antigelz was found in two of jive patients with adenomatous hyperplasia and eight of 11 patients with endometrial adenocarcinoma. A comparable degree of inhibition u~a.sfound with autologow antigen. DNCB skin reactions were found to be strongly positive in patients with adenomatous hyperplasia, and a lesser degree of reactiuity was observed in patients with endomelrial adtnocarcinoma. No correlation was found betuleen leukocyte migration tests and DNCB reactions, and no correlation was observed betureen these tests and the age of the patient, clinical stage of diseax, or histologic grade of the tumor.
A WIDE VARIETY of in vitro tests have been utilized to assess specific and nonspecific cellular hypersensitivity in patients with malignant tumors. Inhibition of leukocyte migration by homologous and autologous tumorassociated antigens has been demonstrated for a presence of cellular hypersenvariety of tumors. ‘-‘The sitivity as measured by leukocyte migration appears to be a frequent phenomenon, and the antigens utilized exhibit considerable specificity for autologous and/or homologous tumors. Nonspecific alteration of cellular hypersensitivity has been measured by phytohemagglutinin stimulation of lymphocytes in vitro’ and by dinitrochlorobenzene (DNCB) skin testing in vivo.8-‘o No clear pattern has emerged from these studies to indicate that depression or enhancement of cellular hypersensitivity is related to the natural history of tumor progression. The purpose of the present study was to measure specific cellular hypersensitivity to tumor-associated From the Departments Pathology, The Mount Recewed for publication Revised
February
Accepted
March
of Obstetrics and Gynecology Sinai School of Medicine. December
antigens with the use of the leukocyte migration test and nonspecific cellular hypersensitivity by skin testing with DNCB in patients with endometrial adenocarcinema. An attempt was made to correlate the degree of cellular hypersensirivity with certain clinical and histologic parameters.
Materials and methods Patients. Five patients with adenomatous hyperplasia, 11 patients with endometrial adenocarcinoma, seven patients with squamous cell carcinoma of the cervix, one patient with hydatidiform mole, and five normal women were studied. All patients and control subjects were tested prior to initiation of therapy except for the adenomatous hyperplasia group who were studied immediately after operation. Leukocyte migration technique. Purified lymphocytes were obtained with the use of a modified Ficolli Hypaque* gradient followed by passage through sucrose to remove contaminating platelets.” Migration assays were performed as previously described,3 and the migration index (M.I.) was calculated as follows:
and
5, I9 75.
area of migration with antigen M.I. = area of migration without antigen
2?, 1976. 18, 1976.
Reprint requests: Dr. David Koff2er, Department of Pathotogy, Mt. Sinai School of Medicine, Fifth Ave. and 100th. St., New York, Neul York 10029.
*Winthrop New York,
370
Labs., Div. of Sterling New York 10016.
Drug
Inc.,
x lOO(%).
90 Park Ave.,
Volume Number
12fi 3
Cellular hypersensitivity with endometrial hyperplasia and adenocarcinoma
Table I. Leukocyte of endometrium
migration
indices
in patients
with adenomatous
Antigel Autologous antigen Adenomatow Die* Hay Pel LeG sto Endometrial Lar Rie Yah
usedfor
Adenocarcinoma of endomehium
and adenocarcinoml
inhibition Squamous
carcinoma
ofwvix
hyperplasia 47.5-t 98.0 95.0 97.1 42.4
(45.8-50.5$) (97.4-98.8) (91.0-99.5) (94.3-98.9) (37.8-44.9)
54.9 95.5 101.9 103.5 45.7
(53.8-56.5) (90.1-104.8) (97.5-106.4) (103.0-103.8) (44.8-47.4)
96.1 89.6 107.4 104.1
(94.2-98.3) (87.7-91.5) (103.4-110.5) (103.9-104.3)
32.2 71.5 40.4 74.8 31 .o 98.8
(28.5-35.7) (69.3-75.8) (38.0-42.5) (69.1-77.3j (29.7-32.5) (92.8-104.7)
25.1 54.3 35.1 89.9 33.9 102.3 60.3 49.5 49.1 72.4 86.4
(24.8-25.7) (48.3-59.1) (30.1-41.3) i80.5-94.3j (32.5-36.5) (97.2-107.5) (59.1-62.3) (46.6-52.3) (47.9-50.83 (67.9-79.0) (81.9-91.0)
107.7 (97.1-110.5) 112.9(111.2-115.5)
103.2 (103.0-103.5) 85.9 (83.2-88.7) 102.9 (101.9-103.8)
adenocarcinoma
Dia PUl Nes
Fou
51.5 (47.3-54.7)
Ros Tho McK Pha
50.1 49.7 87.6 92.3
*Patient tMean *Range
hyperplasia
371
studied. expressed of values
(46.6-53.0) (46.1-54.4) (81.1-98.4) (89.1-95.5)
98.1 (97.4-99.0) 115.0(110.2-120.1) 95.6 (91.7-98.5) 94.2 (91.0-97.7) 95.7 (91.6-98.8) 83.3 (82.8-84.0)
103.1 116.2 92.1 101.9 116.1 92.0 83.1
(99.3-107.0) (109.8-122.9) i90.5-93.7) (99.6-104.1) (113.7-118.5) (90.4-93.2) (81.9-84.5)
as per cent migration. for four experiments.
Antigens. Homogenates of tumor were prepared from autologous and homologous tissues.’ Homogenates obtained from cervical squamous cell carcinoma and ovarian papillary serous cystadenocarcinoma were previously shown to be reactive with leukocytes obtained from patients with homologous tumors. Skin tests. Contact sensitization to DNCB was tested in each patient, and either the skin reactions were recorded as negative or they were graded 1 to 4+ positive.‘”
Results Leukocyte migration experiments. The M.I.‘s for each patient studied from the adenomatous hyperplasia and endometrial adenocarcinoma groups are summarized in Table 1. In addition, no inhibition of leukocyte migration was observed in seven patients with squamous cell carcinoma of the cervix or hydatidiform mole or in five normal women. Skin tests. The results of skin tests are summarized in Table II and compared to the degree of leukocyte migration. All patients with adenomatous hyperplasia had strong DNCB reactions except for one patient who was not reactive. This patient had advanced alcoholic cirrhosis. The skin reaction of the endometrial adenocarcinoma patients was variable and unrelated to the clinical stage of the tumor.
Comment Patients with endometrial carcinoma manifest a high incidence of cellular hypersensitivity, as measured by inhibition of leukocyte migration, to tumor-associated antigens derived from autologous and homologous tumors. The comparable degree of reactivity of autologous and homologous antigens indicate that a group-specific antigen similar to that found in squamous cell carcinoma of the cervix2 and papillary serous cystadenocarcinoma of the ovary3 is involved. The latter extracts, which are active in leukocyte rnigration tests performed in patients with homologous tumors, showed no inhibition of leukocyte migration in patients with endometrial carcinoma or adenomatous hyperplasia, suggesting that three independent antigen systems are operative in inducing cellular hypersensitivity in patients with these gynecologic tumors. The considerable body of clinical and histopathologic evidence that adenomatous hvperplasia is a closely related precursor lesion of endometrial carcinomar3 received further support from these studies. Leukocytes from two of five patients with adenomatous hyperplasia manifested sensitization to antigens derived from endometrial carcinoma as well as to antigens derived from autologous adenomatous hyperplasia tissue. Although insufficient “hyperplasia” antigen was available for testing leukocvtrs from pa-
372
Chen, Cohen, and Koffler
Table II. Summary of clinical features, leukocyte migration, and DNCB skin tests in patients with adenomatous hyperplasia and adenocarcinoma of endometrium Patient
Age
Die Hay Pel Let St0 Lar Rie Yah Dia Pul Nes Fou Ros Tho McK Pha
54 48 39 41 58 55 72 63 62 66 77 64 81 46 61 62
FIG0 Stage*
Hktological gdet
0 0 0 0 0 IA IA IA IA IB IB IB IB II II III
DNCB reaction+
-
4+ 3-t 3+ 0 3+ 2+ 3+ 4+ 0 0 2+ 2+ 3+ 0 1+ 3+
I I I III II I I III I II I
Leukocyte migration8 3+ 0 0 0 3+ 3+ 3+ 3+ 0 3+ 0 2+ 3+ 3+ 1+ 0
*International Federation of Gynecology and Obstetrics classification.” +I, Well-differentiated adenocarcinoma; II, moderately differentiated adenocarcinoma; III, poorly differentiated adenocarcinoma. $DNCB reactions graded negative (0) to strongly positive (4+).
PMigration index of >80 (0), 70 to 80 (l+), 60 to 70 (2+), and ~60 (3+) for inhibition with homologous endometrial carcinoma antigen.
tients with endometrial carcinoma, it is likely that cross-reacting or identical antigen is responsible for the inhibition of leukocyte migration in the two groups of patients. The DNCB skin test for in vivo delayed hypersensitivity was strongly positive in four of five patients with adenomatous hyperplasia, whereas patients with endometrial carcinoma showed a lesser degree of reactivity. This does not appear to be related to the younger mean age of patients with adenomatous hyperplasia inasmuch as strong reactions were observed in elderly patients and negative or weaker reactions were found in several younger patients. Adequate follow-up data were not available to assess the relationship prognosis to either DNCB reactivity or leukocyte migration. Previous studies indicate that in patients with certain tumors there is a correlation between increased survi-
val and positive DNCB reactions.‘” No relationship between either DNCB reaction or leukocyte migration and clinical stage or histologic grade was found in I hr present study. Inhibition of leukocyte migration has been shown to assay “delayed hypersensitivity” as evidenced by skin reaction where the same antigen is used for both the in vivo and in vitro tests. A good correlation was found between the test when streptokinase/streptodornase and purified protein derivative were tested in previously sensitized patients.5 When patients were immunized with keyhole limpet hemocyanin vigorous skin responses were found in patients with significant inhibition of leukocyte migration.“’ In the present study, the lack of correlation between DNCB skin tests and inhibition of leukocyte migration may indicate that DNCB reactions do not necessarily reflect the degree of sensitization to the tumor-associated antigen of endometrial carcinoma. At present, inhibition of leukocyte migration appears to be the most specific and reproducible method for detecting cellular hypersensitivity to tumorassociated antigens. Extracts of tumors derived from the colon,” cutaneous melanomas,’ the breast,” the lung,’ the ovary, 3, 7 and the uterine cervix’ have been shown to possess selective reactivity in the leukocyte migration test. The nature of the antigen responsible for the inhibition of leukocyte migration in patients with gynecologic tumors is presently being studied. The failure of cross-reactivity among antigens derived from tumors of the genital tract in the leukocyte migration test suggest that oncofetal antigens are not of primary importance in this reaction. The absence of inhibition of the extracts when tested with leukocytes from normal women indicates that histocompatibility antigens are probably not involved in this reaction. Preliminary studies indicate that tumor-associated antigens may be detected in fractions of tumor homogenates and may be amenable to concentration in a more purified state.” Studies from several other tumors, breast” and lung carcinoma, ’ indicate that potassium chloride extracts contain antigens reactive in the leukocyte migration test. The leukocyte migration system may provide a basis for isolating tumor-associated antigens which actively sensitize patients, possibly at a stage prior to the development of infiltration.
REFERENCES
1. Boddie, A. W., Carmack, E., Holmes, E., Roth, J. A., and Morton, D. L.: Inhibition of human leukocyte migration in agarose J. Cancer
by KC1 extracts 15: 823, 1975.
of carcinoma
of the lung,
Int.
2. Chen,
S., Koffler,
D., and Cohen,
C. J.: Cellular
hypersen-
sitivity in patients with squamous cell carcinoma of the cervix, 3. Chen,
AM.
J. OBSTET.
S., Koffler,
GYNECOL.
D., and
Cohen,
91, 1975. C. J.: Cell-mediated
121:
Cellular
4.
5.
6.
7.
8.
9.
hypersensitivity
immunity in patients with ovarian carcinoma, AM J. OBsrET. GYNECOL. 115: 467, 1973. Mackie, R. M., Spilg, W. G. S., Thomas, C. E., and Cochran, A. J.: Cell-mediated immunity in patients with malignant melanoma, Br. J. Dermatol. 87: 523, 1972. McCoy, J. L., Jerome, L. F., Dean, J. H., Cannon, C. B., Alford, T. C.. Doering, T., and Herberman, R. B.: Inhibition of leukocyte migration by tumor-associated antigens in soluble extracts of human breast carcinoma, J. Natl. Cancer Inst. 53: 11. 1974. McIllmurray, M. B.. Price, M. R., and Langman, J. S.: Inhibition of leukocyte migration in patients with large intestinal cancer bv extracts prepared from large intestinal tumors and from normal colonic mucosa. Br. J. Cancer 29: 305. 1974. Melnick. H., and Barber, H. R. K.: Cellular immunologic responsiveness to extracts of ovarian epithelial tumors, Gynecol. Oncol. 3: 77, 1975. ‘I‘wome~. P. L., Catalona. W. J., and Chretien, P. B.: Cellular immunity in cured cancer patients. Cancer 33: 433, 1974. Catalona, W. J., and Chretien, P. B.: Abnormalities of quanrnanve drmtrochlorobenzene sensitization in cancer patients-correlation with tumor stage and histology, Cancer
31:
353,
19713.
with endometrial
hyperplasia
and adenocarcinoma
373
10. Morton, D. L., and Eilber, F. R.: Prognostic significance of cutaneous anergy for the surgical treatment of. solid neoplasms, Natl. Cancer Inst. Monogr. 34: 103, I97 1. 11. Bull, D. M., Leibach, J. R.. Williams. M. A.. and Helms. R. A.: Immunity to colon cancer assesseci by antigeninduced inhibition of mixed mononuclear tell migration, Science 181: 957, 1972. 12. Catalona, W. J.. Taylor, P. T., Kabson, ri. S.. and (:hretien, P. B.: A method for dinitrochlorobtr~7~ne contact sensitization-A clinicopathological sruti\ , N. Engl. J. Med. 286: 399, 1972. 13. Gusberg, S. B., and Kaplan, A. I,.: Precursors ot corpus cancer. IV. Adenomatous hyperplasia as stage 0 carcinoma of cndometrium, .4nr. J. ORSTE,I (;YYF.COI.. 87: 662. 1963. 14. Curtis, J. E., and Hersh, E. M.: Cellular immunity in man: Correlation of leukocyte migration inhibition factor formation and delayed hvpersensitivitv. (:cII. Irnmunol. 8: 55, 1973. 15. Faiferman, I., Gleicher, N.. Cohen, C.J., alltl Raffler. D.: Unpublished results. 16. The International Federation of Gvnecology and Obstetrics: Definitions of the different clinical stages of carcinoma of the corpus uteri, Int. I. Gvnccol. Obstet. 9: 172, 1951.
Y.
CARMEL
J.
DAVID
CHEN,
M.D.
COHEN,
M.D.
KOFFLER,
M.D.
New York, New York Cellular hypersensitivity was studied in patients with adenomatous hyperplasia and adenocarcinom.a of the endometrium with the use of dinitrochlorobenzene (DNCB) skzn tests and inhibition of leukocyte migration by homologous and autologous tumor antigen. Inhibition of leukocyte migration by homologous endometrial carcinoma antigelz was found in two of jive patients with adenomatous hyperplasia and eight of 11 patients with endometrial adenocarcinoma. A comparable degree of inhibition u~a.sfound with autologow antigen. DNCB skin reactions were found to be strongly positive in patients with adenomatous hyperplasia, and a lesser degree of reactiuity was observed in patients with endomelrial adtnocarcinoma. No correlation was found betuleen leukocyte migration tests and DNCB reactions, and no correlation was observed betureen these tests and the age of the patient, clinical stage of diseax, or histologic grade of the tumor.
A WIDE VARIETY of in vitro tests have been utilized to assess specific and nonspecific cellular hypersensitivity in patients with malignant tumors. Inhibition of leukocyte migration by homologous and autologous tumorassociated antigens has been demonstrated for a presence of cellular hypersenvariety of tumors. ‘-‘The sitivity as measured by leukocyte migration appears to be a frequent phenomenon, and the antigens utilized exhibit considerable specificity for autologous and/or homologous tumors. Nonspecific alteration of cellular hypersensitivity has been measured by phytohemagglutinin stimulation of lymphocytes in vitro’ and by dinitrochlorobenzene (DNCB) skin testing in vivo.8-‘o No clear pattern has emerged from these studies to indicate that depression or enhancement of cellular hypersensitivity is related to the natural history of tumor progression. The purpose of the present study was to measure specific cellular hypersensitivity to tumor-associated From the Departments Pathology, The Mount Recewed for publication Revised
February
Accepted
March
of Obstetrics and Gynecology Sinai School of Medicine. December
antigens with the use of the leukocyte migration test and nonspecific cellular hypersensitivity by skin testing with DNCB in patients with endometrial adenocarcinema. An attempt was made to correlate the degree of cellular hypersensirivity with certain clinical and histologic parameters.
Materials and methods Patients. Five patients with adenomatous hyperplasia, 11 patients with endometrial adenocarcinoma, seven patients with squamous cell carcinoma of the cervix, one patient with hydatidiform mole, and five normal women were studied. All patients and control subjects were tested prior to initiation of therapy except for the adenomatous hyperplasia group who were studied immediately after operation. Leukocyte migration technique. Purified lymphocytes were obtained with the use of a modified Ficolli Hypaque* gradient followed by passage through sucrose to remove contaminating platelets.” Migration assays were performed as previously described,3 and the migration index (M.I.) was calculated as follows:
and
5, I9 75.
area of migration with antigen M.I. = area of migration without antigen
2?, 1976. 18, 1976.
Reprint requests: Dr. David Koff2er, Department of Pathotogy, Mt. Sinai School of Medicine, Fifth Ave. and 100th. St., New York, Neul York 10029.
*Winthrop New York,
370
Labs., Div. of Sterling New York 10016.
Drug
Inc.,
x lOO(%).
90 Park Ave.,
Volume Number
12fi 3
Cellular hypersensitivity with endometrial hyperplasia and adenocarcinoma
Table I. Leukocyte of endometrium
migration
indices
in patients
with adenomatous
Antigel Autologous antigen Adenomatow Die* Hay Pel LeG sto Endometrial Lar Rie Yah
usedfor
Adenocarcinoma of endomehium
and adenocarcinoml
inhibition Squamous
carcinoma
ofwvix
hyperplasia 47.5-t 98.0 95.0 97.1 42.4
(45.8-50.5$) (97.4-98.8) (91.0-99.5) (94.3-98.9) (37.8-44.9)
54.9 95.5 101.9 103.5 45.7
(53.8-56.5) (90.1-104.8) (97.5-106.4) (103.0-103.8) (44.8-47.4)
96.1 89.6 107.4 104.1
(94.2-98.3) (87.7-91.5) (103.4-110.5) (103.9-104.3)
32.2 71.5 40.4 74.8 31 .o 98.8
(28.5-35.7) (69.3-75.8) (38.0-42.5) (69.1-77.3j (29.7-32.5) (92.8-104.7)
25.1 54.3 35.1 89.9 33.9 102.3 60.3 49.5 49.1 72.4 86.4
(24.8-25.7) (48.3-59.1) (30.1-41.3) i80.5-94.3j (32.5-36.5) (97.2-107.5) (59.1-62.3) (46.6-52.3) (47.9-50.83 (67.9-79.0) (81.9-91.0)
107.7 (97.1-110.5) 112.9(111.2-115.5)
103.2 (103.0-103.5) 85.9 (83.2-88.7) 102.9 (101.9-103.8)
adenocarcinoma
Dia PUl Nes
Fou
51.5 (47.3-54.7)
Ros Tho McK Pha
50.1 49.7 87.6 92.3
*Patient tMean *Range
hyperplasia
371
studied. expressed of values
(46.6-53.0) (46.1-54.4) (81.1-98.4) (89.1-95.5)
98.1 (97.4-99.0) 115.0(110.2-120.1) 95.6 (91.7-98.5) 94.2 (91.0-97.7) 95.7 (91.6-98.8) 83.3 (82.8-84.0)
103.1 116.2 92.1 101.9 116.1 92.0 83.1
(99.3-107.0) (109.8-122.9) i90.5-93.7) (99.6-104.1) (113.7-118.5) (90.4-93.2) (81.9-84.5)
as per cent migration. for four experiments.
Antigens. Homogenates of tumor were prepared from autologous and homologous tissues.’ Homogenates obtained from cervical squamous cell carcinoma and ovarian papillary serous cystadenocarcinoma were previously shown to be reactive with leukocytes obtained from patients with homologous tumors. Skin tests. Contact sensitization to DNCB was tested in each patient, and either the skin reactions were recorded as negative or they were graded 1 to 4+ positive.‘”
Results Leukocyte migration experiments. The M.I.‘s for each patient studied from the adenomatous hyperplasia and endometrial adenocarcinoma groups are summarized in Table 1. In addition, no inhibition of leukocyte migration was observed in seven patients with squamous cell carcinoma of the cervix or hydatidiform mole or in five normal women. Skin tests. The results of skin tests are summarized in Table II and compared to the degree of leukocyte migration. All patients with adenomatous hyperplasia had strong DNCB reactions except for one patient who was not reactive. This patient had advanced alcoholic cirrhosis. The skin reaction of the endometrial adenocarcinoma patients was variable and unrelated to the clinical stage of the tumor.
Comment Patients with endometrial carcinoma manifest a high incidence of cellular hypersensitivity, as measured by inhibition of leukocyte migration, to tumor-associated antigens derived from autologous and homologous tumors. The comparable degree of reactivity of autologous and homologous antigens indicate that a group-specific antigen similar to that found in squamous cell carcinoma of the cervix2 and papillary serous cystadenocarcinoma of the ovary3 is involved. The latter extracts, which are active in leukocyte rnigration tests performed in patients with homologous tumors, showed no inhibition of leukocyte migration in patients with endometrial carcinoma or adenomatous hyperplasia, suggesting that three independent antigen systems are operative in inducing cellular hypersensitivity in patients with these gynecologic tumors. The considerable body of clinical and histopathologic evidence that adenomatous hvperplasia is a closely related precursor lesion of endometrial carcinomar3 received further support from these studies. Leukocytes from two of five patients with adenomatous hyperplasia manifested sensitization to antigens derived from endometrial carcinoma as well as to antigens derived from autologous adenomatous hyperplasia tissue. Although insufficient “hyperplasia” antigen was available for testing leukocvtrs from pa-
372
Chen, Cohen, and Koffler
Table II. Summary of clinical features, leukocyte migration, and DNCB skin tests in patients with adenomatous hyperplasia and adenocarcinoma of endometrium Patient
Age
Die Hay Pel Let St0 Lar Rie Yah Dia Pul Nes Fou Ros Tho McK Pha
54 48 39 41 58 55 72 63 62 66 77 64 81 46 61 62
FIG0 Stage*
Hktological gdet
0 0 0 0 0 IA IA IA IA IB IB IB IB II II III
DNCB reaction+
-
4+ 3-t 3+ 0 3+ 2+ 3+ 4+ 0 0 2+ 2+ 3+ 0 1+ 3+
I I I III II I I III I II I
Leukocyte migration8 3+ 0 0 0 3+ 3+ 3+ 3+ 0 3+ 0 2+ 3+ 3+ 1+ 0
*International Federation of Gynecology and Obstetrics classification.” +I, Well-differentiated adenocarcinoma; II, moderately differentiated adenocarcinoma; III, poorly differentiated adenocarcinoma. $DNCB reactions graded negative (0) to strongly positive (4+).
PMigration index of >80 (0), 70 to 80 (l+), 60 to 70 (2+), and ~60 (3+) for inhibition with homologous endometrial carcinoma antigen.
tients with endometrial carcinoma, it is likely that cross-reacting or identical antigen is responsible for the inhibition of leukocyte migration in the two groups of patients. The DNCB skin test for in vivo delayed hypersensitivity was strongly positive in four of five patients with adenomatous hyperplasia, whereas patients with endometrial carcinoma showed a lesser degree of reactivity. This does not appear to be related to the younger mean age of patients with adenomatous hyperplasia inasmuch as strong reactions were observed in elderly patients and negative or weaker reactions were found in several younger patients. Adequate follow-up data were not available to assess the relationship prognosis to either DNCB reactivity or leukocyte migration. Previous studies indicate that in patients with certain tumors there is a correlation between increased survi-
val and positive DNCB reactions.‘” No relationship between either DNCB reaction or leukocyte migration and clinical stage or histologic grade was found in I hr present study. Inhibition of leukocyte migration has been shown to assay “delayed hypersensitivity” as evidenced by skin reaction where the same antigen is used for both the in vivo and in vitro tests. A good correlation was found between the test when streptokinase/streptodornase and purified protein derivative were tested in previously sensitized patients.5 When patients were immunized with keyhole limpet hemocyanin vigorous skin responses were found in patients with significant inhibition of leukocyte migration.“’ In the present study, the lack of correlation between DNCB skin tests and inhibition of leukocyte migration may indicate that DNCB reactions do not necessarily reflect the degree of sensitization to the tumor-associated antigen of endometrial carcinoma. At present, inhibition of leukocyte migration appears to be the most specific and reproducible method for detecting cellular hypersensitivity to tumorassociated antigens. Extracts of tumors derived from the colon,” cutaneous melanomas,’ the breast,” the lung,’ the ovary, 3, 7 and the uterine cervix’ have been shown to possess selective reactivity in the leukocyte migration test. The nature of the antigen responsible for the inhibition of leukocyte migration in patients with gynecologic tumors is presently being studied. The failure of cross-reactivity among antigens derived from tumors of the genital tract in the leukocyte migration test suggest that oncofetal antigens are not of primary importance in this reaction. The absence of inhibition of the extracts when tested with leukocytes from normal women indicates that histocompatibility antigens are probably not involved in this reaction. Preliminary studies indicate that tumor-associated antigens may be detected in fractions of tumor homogenates and may be amenable to concentration in a more purified state.” Studies from several other tumors, breast” and lung carcinoma, ’ indicate that potassium chloride extracts contain antigens reactive in the leukocyte migration test. The leukocyte migration system may provide a basis for isolating tumor-associated antigens which actively sensitize patients, possibly at a stage prior to the development of infiltration.
REFERENCES
1. Boddie, A. W., Carmack, E., Holmes, E., Roth, J. A., and Morton, D. L.: Inhibition of human leukocyte migration in agarose J. Cancer
by KC1 extracts 15: 823, 1975.
of carcinoma
of the lung,
Int.
2. Chen,
S., Koffler,
D., and Cohen,
C. J.: Cellular
hypersen-
sitivity in patients with squamous cell carcinoma of the cervix, 3. Chen,
AM.
J. OBSTET.
S., Koffler,
GYNECOL.
D., and
Cohen,
91, 1975. C. J.: Cell-mediated
121:
Cellular
4.
5.
6.
7.
8.
9.
hypersensitivity
immunity in patients with ovarian carcinoma, AM J. OBsrET. GYNECOL. 115: 467, 1973. Mackie, R. M., Spilg, W. G. S., Thomas, C. E., and Cochran, A. J.: Cell-mediated immunity in patients with malignant melanoma, Br. J. Dermatol. 87: 523, 1972. McCoy, J. L., Jerome, L. F., Dean, J. H., Cannon, C. B., Alford, T. C.. Doering, T., and Herberman, R. B.: Inhibition of leukocyte migration by tumor-associated antigens in soluble extracts of human breast carcinoma, J. Natl. Cancer Inst. 53: 11. 1974. McIllmurray, M. B.. Price, M. R., and Langman, J. S.: Inhibition of leukocyte migration in patients with large intestinal cancer bv extracts prepared from large intestinal tumors and from normal colonic mucosa. Br. J. Cancer 29: 305. 1974. Melnick. H., and Barber, H. R. K.: Cellular immunologic responsiveness to extracts of ovarian epithelial tumors, Gynecol. Oncol. 3: 77, 1975. ‘I‘wome~. P. L., Catalona. W. J., and Chretien, P. B.: Cellular immunity in cured cancer patients. Cancer 33: 433, 1974. Catalona, W. J., and Chretien, P. B.: Abnormalities of quanrnanve drmtrochlorobenzene sensitization in cancer patients-correlation with tumor stage and histology, Cancer
31:
353,
19713.
with endometrial
hyperplasia
and adenocarcinoma
373
10. Morton, D. L., and Eilber, F. R.: Prognostic significance of cutaneous anergy for the surgical treatment of. solid neoplasms, Natl. Cancer Inst. Monogr. 34: 103, I97 1. 11. Bull, D. M., Leibach, J. R.. Williams. M. A.. and Helms. R. A.: Immunity to colon cancer assesseci by antigeninduced inhibition of mixed mononuclear tell migration, Science 181: 957, 1972. 12. Catalona, W. J.. Taylor, P. T., Kabson, ri. S.. and (:hretien, P. B.: A method for dinitrochlorobtr~7~ne contact sensitization-A clinicopathological sruti\ , N. Engl. J. Med. 286: 399, 1972. 13. Gusberg, S. B., and Kaplan, A. I,.: Precursors ot corpus cancer. IV. Adenomatous hyperplasia as stage 0 carcinoma of cndometrium, .4nr. J. ORSTE,I (;YYF.COI.. 87: 662. 1963. 14. Curtis, J. E., and Hersh, E. M.: Cellular immunity in man: Correlation of leukocyte migration inhibition factor formation and delayed hvpersensitivitv. (:cII. Irnmunol. 8: 55, 1973. 15. Faiferman, I., Gleicher, N.. Cohen, C.J., alltl Raffler. D.: Unpublished results. 16. The International Federation of Gvnecology and Obstetrics: Definitions of the different clinical stages of carcinoma of the corpus uteri, Int. I. Gvnccol. Obstet. 9: 172, 1951.