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Immune complex deposition in thyroid carcinoma associated with chronic thyroiditis
CLtNfCAL
IMMUNOLOGY
Immune
AND
Complex Deposition in Thyroid Carcinoma Associated with Chronic Thyroiditisl
ALBERT Department
4, 101-107 (1975)
IMMUNOPATHOLOGY
E. KALDERON, HENDRIK A. BOGAARS, AND ISRAEL DIAMOND
of Pathology, Roger Williums Generul Hospitul und Section of Pathology, Division of BiologicuI und Medical Sciences, Brown Uni\nersity, Providence, Rhode Island 02908
Received September 24, 1974 A case of unilateral multifocal carcinoma of the thyroid associated with chronic lymphocytic thyroiditis was studied by electron microscopy and by immunofluorescence. Immune complex deposits were demonstrated in the follicular basement membrane (FBM) correlating with positive immunofluorescent staining with anti-lgG, anti-C3, and antithyroglobulin. This report provides evidence that a humoral immune mechanism with immune complex deposition, such as previously described in Hashimoto’s thyroiditis, may also play a role in the pathogenesis of thyroiditis associated with carcinoma of the thyroid. An attempt is made to explain the selective deposition of immune complexes in the FBM.
INTRODUCTION
In an earlier study cl), alterations of the follicular basement membrane (FBM) associated with electron-dense deposits were described in eight cases of Hashimoto’s thyroiditis. The deposits correlated well with the immunofluorescent staining pattern of granular deposition of IgG and C3 in one case of Hashimoto’s thyroiditis associated with systemic lupus erythematosus and, therefore, were regarded as immune complexes. Since then, further studies have shown a higher degree of correlation between electron-microscopic observations and immunofluorescent studies in several cases of Hashimoto’s thyroiditis and in some cases of Graves’ disease as well. Recently, similar deposits were observed in a case of multicentric papillary carcinoma of the left lobe of the thyroid coexisting with focal chronic lymphocytic thyroiditis. This report describes the existence of immune complexes in the FBM of neoplastic follicles in areas of heavy lymphocyte and plasma cell infiltration. An attempt is made to explain the selective deposition of immune complexes in altered FBM. CASE REPORT
A 25-yr-old Caucasian female was admitted because of a mass involving the left lobe of the thyroid. The patient had noticed enlargement of the neck 4 yr previously and was treated with desiccated thyroid without appreciable change in the size of the mass. Elective surgery was performed because of the persistence of the lesion in spite of therapy. Preoperative thyroid-function tests were ’ Supported in part by a grant from the National Cancer Institute (CA 13943 and CA 14379) and from the Research Corporation, Brown-Hazen Fund. 101 Copyright @ 1975 by Academic Press, Inc. All rights of reproduction in any form reserved.
102
KALDERON,
BOGAARS
AND
DIAMOND
within normal limits. Antibody titers were not available. A scintiscan after oral administration of 50 f.cCi of sodium iodide13’ I revealed a cold, nonfunctioning area corresponding to the enlarged left lobe of the thyroid. A total left lobectomy with removal of the isthmus and a partial right-lobe resection was performed. METHODS
For light microscopy, paraffin-embedded tissue was cut and stained with hematoxylin and eosin. For electron microscopy, tissue samples were minced in small blocks of approximately I mm in size and immersed in cold 2.5% glutaraldehyde prepared in 0.1 M cacodylate buffer, pH 7.4, for 4 hr: washed in buffer, and postfixed in 1% osmium tetroxide for 1 hr; dehydrated, and embedded in resin. Thin sections, cut with an LKB ultramicrotome supported on 200-mesh copper grids, were stained with a combination of uranyl acetate and lead citrate and examined with an RCA EMU 4E electron microscope at 75 kV. Thyroid tissue obtained at operation was quick frozen in liquid nitrogen and stored at -70°C until examined. The tissue was cut at 5 pm on an IEC cryostat at -20°C. Sections were then thawed at room temperature and fixed for 10 min in acetone. After washing in three changes of phosphate-buffered saline (0.0 1 M, pH 7.2), the sections were covered with fluorescein-conjugated (Hyland Laboratories, Los Angeles, CA and Hoechst Pharmaceuticals, Somerville, NJ) goat and rabbit antisera against human IgG, IgA, IgM, C3, fibrinogen, albumin, and thyroglobulin and incubated at room temperature for 30 min. The antisera were tested for specificity by immunoelectrophoresis against normal human serum. Immunologic sensitivity was tested according to Beutner et ul. (2). Conjugates were initially used in working dilutions of 0.25-0.50 units/ml. Subsequently. examinations were repeated using dilutions of 1 unit/ml. All antisera were absorbed before use with mouse liver powder. After incubation, sections were washed in three changes of phosphate-buffered saline for a total of 15 min and mounted in phosphate-buffered glycerol. Examinations were carried out immediately and after 18 hr of storage at 4°C with a Leitz microscope equipped with fluorescent attachment using an HBO 200 mercury vapor lamp, UGI exciter filter, K430 barrier filter, and a cardioid dark-field condenser. Washed-unstained and unwashed-unstained sections were used as controls. Blocking procedures were carried out by prior incubation of sections with unconjugated antisera against human IgG, IgA, and IgM followed by the conjugated antisera. Thyroid tissue obtained from another gland with no evidence of thyroiditis, treated in the same manner. served as control. RESULTS
Light Microscopy
Sections stained with hematoxylin and eosin revealed a multicentric papillary carcinoma involving most of the left lobe (Fig. 1). There was an associated focal chronic lymphocytic thyroiditis. The segment of the right lobe and the isthmus were free of tumor and of thyroiditis. Foci of pleomorphic papillary structures
IMMUNE
DEPOSITS
IN THYROID
CARCINOMA
103
FIG. 1. Papillary carcinoma of the left lobe. Note psamomma bodies and relatively uninvolved follicles surrounded by round inflammatory cells. Hematoxylin and eosin. x 250.
arising from disrupted follicles were alternating with fields of apparently normal thyroid follicles. Neoplastic foci with psammoma bodies were often surrounded by an infiltrate composed of lymphocytes and plasma cells. There were no germinative centers. In areas of heavy infiltration, the follicles were small and
FIG. 2. Basal portion of a thyroid follicular cell. The basement membrane is thick. Several electron-dense deposits can be seen (arrows) within the thickness of the BM. X23,000.
104
FIG. (arrows)
KALDERON,
3. in
Basal close
portion proximity
deprived of colloid. sent.
of
BOGAARS
a thyroid cell. Thickening to a plasma cell which
Oncocytic
AND
has
transformation
DIAMOND
and lamellation penetrated
the
of the follicular
and interstitial
BM
with space.
deposit5 X1X,%)0.
fibrosis were ab-
In areas of dense infiltration, neoplastic and apparently well-differentiated adjacent follicles had an irregular, thick FBM which followed the convolutions of the basal plasma membrane of the thyroid cells. The thickening of the FBM was due to excessive accumulation of basement membranelike material producing at times multilayering. Electron-dense deposits of varying sizes were frequently seen contrasting with the less electron-dense surrounding basement membrane (BM) material (Fig. 2). Apposition of plasma cells to the FBM was often observed (Fig. 3). No FBM deposits were observed in areas devoid of interstitial in-
FIG;. 4. Left some folliclex.
lobe of the thyroid Y 250.
stained
with
anti-IgG.
Segmental
granular
FBM
staining
is noted
in
IMMUNE
DEPOSITS
IN
FIG. 5. Fluorescent staining with anti-thyroglobulin tercellular spaces, and the BM. x 250.
THYROID
distributed
105
CARCINOMA
along
the apical
cell border,
filtration. The vascular basement membrane of adjacent capillaries appearance and no deposits were encountered.
the in-
was normal in
By direct immunofluorescence, the presence in the FBM area of thyroglobulin, IgG, C3, and rarely IgM was demonstrated in the majority of neoplastic follicles. The staining pattern, which was coarsely granular, clearly outlined the FBM (Fig. 4). In some follicles, the presence of thyroglobulin was particularly prominent due to staining of apical cell borders producing double lines, interconnected by lines staining the intercellular spaces (Fig. 5). C3 was also present in a finely granular pattern (Fig. 6). There was no FBM localization of IgA, IgE, albumin, or fibrinogen. Thyroglobulin, and to a lesser extent IgG, IgA. and IgM, was also occasionally observed in the interstitium, particularly around follicles displaying BM fluorescence. In addition, there was intracytoplasmic staining for IgG, IgM, and thyroglobulin in the interstitial plasma cells and lymphocytes.
FIG.
6. Granular
fluorescent
staining
of the FBM
with
anti-C?.
X 250.
106
KALDERON.
BOGAARS
AND
DIAMOND
The control tissue showed no specific staining with any of the conjugates except for thyroglobulin staining of the intrafollicular colloid. DISCUSSION This study has demonstrated the presence of thyroglobulin, IgG, and C3 in the BM of neoplastic follicles and provides strong evidence that the deposits observed by electron microscopy are antigen-antibody complexes. The demonstration by immunofluorescence of thyroglobulin in the perifollicular as well as in intercellular spaces suggest escape of the thyroglobulin from follicular lumina. In addition, cytoplasmic staining obtained in some cells of the interstitial infiltrate for thyroglobulin and IgG implicates the plasma cells of the infiltrate as the source of antibodies against thyroglobulin. Similar observations were reported earlier by Mellors et al. (3) in a case of chronic thyroiditis. The presence of chronic lymphocytic thyroiditis in association with multifocal papillary carcinoma poses the inescapable question as to which of the conditions arose first. A high incidence of chronic lymphocytic thyroiditis associated with carcinoma of the thyroid gland has been reported by several authors (4.5). Hirabayashi and Lindsay (5) attributed the development of chronic thyroiditis to antigens produced by the neoplastic thyroid cells. Goudie I 61, acknowledging the existence of antigen-deficient thyroid carcinomas. regarded thyroglobulin from follicles damaged by the neoplastic process as the immunogen responsible for the development of chronic thyroiditis. Neither of these considerations. however, has taken into account the possible release by neoplastic cells of an altered thyroglobulin capable of eliciting an immune reaction with eventual local production of immune complexes. Indeed, in animals, the occurrence of immune complex formation with heterologous or homologous altered thyroglobulin and the transient presence of these complexes in the circulation is well established (7). Deposition of immunoglobulins and thyroglobulin in the glomeruli of animals with induced autoimmune thyroiditis and also in some patients with chronic thyroiditis (8) suggest that antibody-antigen complexes do circulate and have the potential of being retained in tissues. Weigle (8) demonstrated the presence 01’ immune complexes in the serum and urine of rabbits immunized with either iiitered homologous or heterlogous thyroglobulin and postulated that they may cause tissue damage. Although complement-fixing antigen-antibody complexes were earlier reported by Koffler et crl. (91 within the colloid of cases of Hashimoto thyroiditis, the localization of thyroglobulin-antibody complexes in the FBM has not been described until recently (1). The factors leading to complex deposition and their pathogenic significance are not yet known. A mechanism similar to that proposed by Cochrane (10) for immune complex deposition in the vascular BM of the kidney appears unlikely in view of the apparent affinity of thyroglobulin-antibody complexes for the FBM alone. We would like to come forward with a working hypothesis of dual coexistence of a damaged BM and availability of locally formed or circulating complexes to explain the selective deposition of immune complexes in the FBM. A large body of evidence indicates that the BM is secreted and maintained by epithelial cells in a variety of tissues (1 1,lZ) including endocrine epithelia ( 141
IMMUNE
DEPOSITS
IN
THYROID
CARCINOMA
107
whereas vascular BM is of mesenchymal origin. It has also been shown that a variety of traumatic insults may initiate as a protective response synthesis of abnormal amounts of BM material (15) resulting in thickening, lamellation, and intercellular extension of the BM. The newly generated and perhaps biochemically altered BM may serve as a selective attractant for circulating, or more likely, locally formed immune complexes in areas of thyroglobulin leakage and antibody formation. The apparent affinity of the complexes for the FBM and the conspicuous lack of deposits in the vascular BM support this view. Altered BM may represent a pull factor whereas the amount and rate of formation of circulating soluble complexes capable of crossing the vascular BM constitute a push factor. It becomes apparent that in order to have immune complex deposition, the pull and push factor should coexist. Indeed, the absence of immune complexes in the FBM of noninfiltrated areas and the absence of deposits in the nonaltered vascular BM favor this pathogenic mechanism. The unilateral nature of chronic lymphocytic thyroiditis in this case suggest that it might be a secondary response to neoplastic transformation of the follicular epithelium of the left lobe. This report provides evidence that a humoral immune mechanism other than cell-mediated immunity directed against thyroglobulin (16,17) with immune cnmplex deposition such as has been implicated in Hashimoto’s thyroiditis (1) may also play a role in the pathogenesis of thyroiditis associated with carcinoma of the thyroid. ACKNOWLEDGMENTS We wish to thank the technical assistance of Mr. G. Jolly and Mrs. L. Aleszczyk.
REFERENCES I. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
Kalderon, A. E., Bogaars, H. A., and Diamond, I., Amer. J. Med. 55, 485, 1973. Beutner, E. H.. Sepulveda, M. R., and Barnett, E. V.. BnfI. WHO 39, 587, 1968. Mellors, R. C., Brzosko, W. J., and Sonkin, L. S.. Amer. J. Puthol. 41, 425, 1962. Woolner, L. B., McConahey, W. M.. and Beahrs, 0. H.. J. C/in. Endotrino!. 19, 53, 1959. Hirabayashi, R. N., and Lindsay, S., In “International Colloquium on Tumors of the Thyroid Gland”, Marseille, 1964. (A. Appaix. Ed.), pp. 292-298, American Elsevier, New York. 1966. Goudie, R. B., ln “International Colloquium on Tumors of the Thyroid Gland”, Marseille, 1964, (A. Appaix, Ed.), pp. 272-291, American Elsevier, New York, 1966. Weigle, W. O., In “Pathology Annual,” (S. C. Sommers, Ed), pp. 329-347, Appleton Century Crofts, New York, 1973. Weigle. W. O., and Nakamura, R. M., C/in. Exp. Imm~nol. 4, 645, 1969. Koffler. D., and Friedman, A. H., Lab. Inrj~sr. 13, 239, 1964. Cochrane, C. G., J. Exp. Med. 134, 75s, 1971. Pierce, G. B., Beals, T. F., Ram, J. S., and Midgley, A. R., Amer. J. Patho/. 45, 929, 1964. Pierce, G. B. Midgley, A. R., and Ram, J. S., J. Exp. Med. 117, 339, 1963. Pierce, G. B., and Nakane, P. K., Lab. Invest. 17, 499, 1967. Lever, J. D., J. Biophys. Biochem. Cytol. 2, 293, 1956. Pierce, G. B., Nakane, P. K.. Lab. Invest. 21, 27, 1969. Delepesse, G., Duchateau, J., Collet, H., Govaersts, A., and Bastenie, P. A., C/in. Exp. Immunol. 12, 439, 1972. Lamki, L., Row, W., and Volpe, R., J. C/in. Endou;not. Metab. 37, 358, 1973.
IMMUNOLOGY
Immune
AND
Complex Deposition in Thyroid Carcinoma Associated with Chronic Thyroiditisl
ALBERT Department
4, 101-107 (1975)
IMMUNOPATHOLOGY
E. KALDERON, HENDRIK A. BOGAARS, AND ISRAEL DIAMOND
of Pathology, Roger Williums Generul Hospitul und Section of Pathology, Division of BiologicuI und Medical Sciences, Brown Uni\nersity, Providence, Rhode Island 02908
Received September 24, 1974 A case of unilateral multifocal carcinoma of the thyroid associated with chronic lymphocytic thyroiditis was studied by electron microscopy and by immunofluorescence. Immune complex deposits were demonstrated in the follicular basement membrane (FBM) correlating with positive immunofluorescent staining with anti-lgG, anti-C3, and antithyroglobulin. This report provides evidence that a humoral immune mechanism with immune complex deposition, such as previously described in Hashimoto’s thyroiditis, may also play a role in the pathogenesis of thyroiditis associated with carcinoma of the thyroid. An attempt is made to explain the selective deposition of immune complexes in the FBM.
INTRODUCTION
In an earlier study cl), alterations of the follicular basement membrane (FBM) associated with electron-dense deposits were described in eight cases of Hashimoto’s thyroiditis. The deposits correlated well with the immunofluorescent staining pattern of granular deposition of IgG and C3 in one case of Hashimoto’s thyroiditis associated with systemic lupus erythematosus and, therefore, were regarded as immune complexes. Since then, further studies have shown a higher degree of correlation between electron-microscopic observations and immunofluorescent studies in several cases of Hashimoto’s thyroiditis and in some cases of Graves’ disease as well. Recently, similar deposits were observed in a case of multicentric papillary carcinoma of the left lobe of the thyroid coexisting with focal chronic lymphocytic thyroiditis. This report describes the existence of immune complexes in the FBM of neoplastic follicles in areas of heavy lymphocyte and plasma cell infiltration. An attempt is made to explain the selective deposition of immune complexes in altered FBM. CASE REPORT
A 25-yr-old Caucasian female was admitted because of a mass involving the left lobe of the thyroid. The patient had noticed enlargement of the neck 4 yr previously and was treated with desiccated thyroid without appreciable change in the size of the mass. Elective surgery was performed because of the persistence of the lesion in spite of therapy. Preoperative thyroid-function tests were ’ Supported in part by a grant from the National Cancer Institute (CA 13943 and CA 14379) and from the Research Corporation, Brown-Hazen Fund. 101 Copyright @ 1975 by Academic Press, Inc. All rights of reproduction in any form reserved.
102
KALDERON,
BOGAARS
AND
DIAMOND
within normal limits. Antibody titers were not available. A scintiscan after oral administration of 50 f.cCi of sodium iodide13’ I revealed a cold, nonfunctioning area corresponding to the enlarged left lobe of the thyroid. A total left lobectomy with removal of the isthmus and a partial right-lobe resection was performed. METHODS
For light microscopy, paraffin-embedded tissue was cut and stained with hematoxylin and eosin. For electron microscopy, tissue samples were minced in small blocks of approximately I mm in size and immersed in cold 2.5% glutaraldehyde prepared in 0.1 M cacodylate buffer, pH 7.4, for 4 hr: washed in buffer, and postfixed in 1% osmium tetroxide for 1 hr; dehydrated, and embedded in resin. Thin sections, cut with an LKB ultramicrotome supported on 200-mesh copper grids, were stained with a combination of uranyl acetate and lead citrate and examined with an RCA EMU 4E electron microscope at 75 kV. Thyroid tissue obtained at operation was quick frozen in liquid nitrogen and stored at -70°C until examined. The tissue was cut at 5 pm on an IEC cryostat at -20°C. Sections were then thawed at room temperature and fixed for 10 min in acetone. After washing in three changes of phosphate-buffered saline (0.0 1 M, pH 7.2), the sections were covered with fluorescein-conjugated (Hyland Laboratories, Los Angeles, CA and Hoechst Pharmaceuticals, Somerville, NJ) goat and rabbit antisera against human IgG, IgA, IgM, C3, fibrinogen, albumin, and thyroglobulin and incubated at room temperature for 30 min. The antisera were tested for specificity by immunoelectrophoresis against normal human serum. Immunologic sensitivity was tested according to Beutner et ul. (2). Conjugates were initially used in working dilutions of 0.25-0.50 units/ml. Subsequently. examinations were repeated using dilutions of 1 unit/ml. All antisera were absorbed before use with mouse liver powder. After incubation, sections were washed in three changes of phosphate-buffered saline for a total of 15 min and mounted in phosphate-buffered glycerol. Examinations were carried out immediately and after 18 hr of storage at 4°C with a Leitz microscope equipped with fluorescent attachment using an HBO 200 mercury vapor lamp, UGI exciter filter, K430 barrier filter, and a cardioid dark-field condenser. Washed-unstained and unwashed-unstained sections were used as controls. Blocking procedures were carried out by prior incubation of sections with unconjugated antisera against human IgG, IgA, and IgM followed by the conjugated antisera. Thyroid tissue obtained from another gland with no evidence of thyroiditis, treated in the same manner. served as control. RESULTS
Light Microscopy
Sections stained with hematoxylin and eosin revealed a multicentric papillary carcinoma involving most of the left lobe (Fig. 1). There was an associated focal chronic lymphocytic thyroiditis. The segment of the right lobe and the isthmus were free of tumor and of thyroiditis. Foci of pleomorphic papillary structures
IMMUNE
DEPOSITS
IN THYROID
CARCINOMA
103
FIG. 1. Papillary carcinoma of the left lobe. Note psamomma bodies and relatively uninvolved follicles surrounded by round inflammatory cells. Hematoxylin and eosin. x 250.
arising from disrupted follicles were alternating with fields of apparently normal thyroid follicles. Neoplastic foci with psammoma bodies were often surrounded by an infiltrate composed of lymphocytes and plasma cells. There were no germinative centers. In areas of heavy infiltration, the follicles were small and
FIG. 2. Basal portion of a thyroid follicular cell. The basement membrane is thick. Several electron-dense deposits can be seen (arrows) within the thickness of the BM. X23,000.
104
FIG. (arrows)
KALDERON,
3. in
Basal close
portion proximity
deprived of colloid. sent.
of
BOGAARS
a thyroid cell. Thickening to a plasma cell which
Oncocytic
AND
has
transformation
DIAMOND
and lamellation penetrated
the
of the follicular
and interstitial
BM
with space.
deposit5 X1X,%)0.
fibrosis were ab-
In areas of dense infiltration, neoplastic and apparently well-differentiated adjacent follicles had an irregular, thick FBM which followed the convolutions of the basal plasma membrane of the thyroid cells. The thickening of the FBM was due to excessive accumulation of basement membranelike material producing at times multilayering. Electron-dense deposits of varying sizes were frequently seen contrasting with the less electron-dense surrounding basement membrane (BM) material (Fig. 2). Apposition of plasma cells to the FBM was often observed (Fig. 3). No FBM deposits were observed in areas devoid of interstitial in-
FIG;. 4. Left some folliclex.
lobe of the thyroid Y 250.
stained
with
anti-IgG.
Segmental
granular
FBM
staining
is noted
in
IMMUNE
DEPOSITS
IN
FIG. 5. Fluorescent staining with anti-thyroglobulin tercellular spaces, and the BM. x 250.
THYROID
distributed
105
CARCINOMA
along
the apical
cell border,
filtration. The vascular basement membrane of adjacent capillaries appearance and no deposits were encountered.
the in-
was normal in
By direct immunofluorescence, the presence in the FBM area of thyroglobulin, IgG, C3, and rarely IgM was demonstrated in the majority of neoplastic follicles. The staining pattern, which was coarsely granular, clearly outlined the FBM (Fig. 4). In some follicles, the presence of thyroglobulin was particularly prominent due to staining of apical cell borders producing double lines, interconnected by lines staining the intercellular spaces (Fig. 5). C3 was also present in a finely granular pattern (Fig. 6). There was no FBM localization of IgA, IgE, albumin, or fibrinogen. Thyroglobulin, and to a lesser extent IgG, IgA. and IgM, was also occasionally observed in the interstitium, particularly around follicles displaying BM fluorescence. In addition, there was intracytoplasmic staining for IgG, IgM, and thyroglobulin in the interstitial plasma cells and lymphocytes.
FIG.
6. Granular
fluorescent
staining
of the FBM
with
anti-C?.
X 250.
106
KALDERON.
BOGAARS
AND
DIAMOND
The control tissue showed no specific staining with any of the conjugates except for thyroglobulin staining of the intrafollicular colloid. DISCUSSION This study has demonstrated the presence of thyroglobulin, IgG, and C3 in the BM of neoplastic follicles and provides strong evidence that the deposits observed by electron microscopy are antigen-antibody complexes. The demonstration by immunofluorescence of thyroglobulin in the perifollicular as well as in intercellular spaces suggest escape of the thyroglobulin from follicular lumina. In addition, cytoplasmic staining obtained in some cells of the interstitial infiltrate for thyroglobulin and IgG implicates the plasma cells of the infiltrate as the source of antibodies against thyroglobulin. Similar observations were reported earlier by Mellors et al. (3) in a case of chronic thyroiditis. The presence of chronic lymphocytic thyroiditis in association with multifocal papillary carcinoma poses the inescapable question as to which of the conditions arose first. A high incidence of chronic lymphocytic thyroiditis associated with carcinoma of the thyroid gland has been reported by several authors (4.5). Hirabayashi and Lindsay (5) attributed the development of chronic thyroiditis to antigens produced by the neoplastic thyroid cells. Goudie I 61, acknowledging the existence of antigen-deficient thyroid carcinomas. regarded thyroglobulin from follicles damaged by the neoplastic process as the immunogen responsible for the development of chronic thyroiditis. Neither of these considerations. however, has taken into account the possible release by neoplastic cells of an altered thyroglobulin capable of eliciting an immune reaction with eventual local production of immune complexes. Indeed, in animals, the occurrence of immune complex formation with heterologous or homologous altered thyroglobulin and the transient presence of these complexes in the circulation is well established (7). Deposition of immunoglobulins and thyroglobulin in the glomeruli of animals with induced autoimmune thyroiditis and also in some patients with chronic thyroiditis (8) suggest that antibody-antigen complexes do circulate and have the potential of being retained in tissues. Weigle (8) demonstrated the presence 01’ immune complexes in the serum and urine of rabbits immunized with either iiitered homologous or heterlogous thyroglobulin and postulated that they may cause tissue damage. Although complement-fixing antigen-antibody complexes were earlier reported by Koffler et crl. (91 within the colloid of cases of Hashimoto thyroiditis, the localization of thyroglobulin-antibody complexes in the FBM has not been described until recently (1). The factors leading to complex deposition and their pathogenic significance are not yet known. A mechanism similar to that proposed by Cochrane (10) for immune complex deposition in the vascular BM of the kidney appears unlikely in view of the apparent affinity of thyroglobulin-antibody complexes for the FBM alone. We would like to come forward with a working hypothesis of dual coexistence of a damaged BM and availability of locally formed or circulating complexes to explain the selective deposition of immune complexes in the FBM. A large body of evidence indicates that the BM is secreted and maintained by epithelial cells in a variety of tissues (1 1,lZ) including endocrine epithelia ( 141
IMMUNE
DEPOSITS
IN
THYROID
CARCINOMA
107
whereas vascular BM is of mesenchymal origin. It has also been shown that a variety of traumatic insults may initiate as a protective response synthesis of abnormal amounts of BM material (15) resulting in thickening, lamellation, and intercellular extension of the BM. The newly generated and perhaps biochemically altered BM may serve as a selective attractant for circulating, or more likely, locally formed immune complexes in areas of thyroglobulin leakage and antibody formation. The apparent affinity of the complexes for the FBM and the conspicuous lack of deposits in the vascular BM support this view. Altered BM may represent a pull factor whereas the amount and rate of formation of circulating soluble complexes capable of crossing the vascular BM constitute a push factor. It becomes apparent that in order to have immune complex deposition, the pull and push factor should coexist. Indeed, the absence of immune complexes in the FBM of noninfiltrated areas and the absence of deposits in the nonaltered vascular BM favor this pathogenic mechanism. The unilateral nature of chronic lymphocytic thyroiditis in this case suggest that it might be a secondary response to neoplastic transformation of the follicular epithelium of the left lobe. This report provides evidence that a humoral immune mechanism other than cell-mediated immunity directed against thyroglobulin (16,17) with immune cnmplex deposition such as has been implicated in Hashimoto’s thyroiditis (1) may also play a role in the pathogenesis of thyroiditis associated with carcinoma of the thyroid. ACKNOWLEDGMENTS We wish to thank the technical assistance of Mr. G. Jolly and Mrs. L. Aleszczyk.
REFERENCES I. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
Kalderon, A. E., Bogaars, H. A., and Diamond, I., Amer. J. Med. 55, 485, 1973. Beutner, E. H.. Sepulveda, M. R., and Barnett, E. V.. BnfI. WHO 39, 587, 1968. Mellors, R. C., Brzosko, W. J., and Sonkin, L. S.. Amer. J. Puthol. 41, 425, 1962. Woolner, L. B., McConahey, W. M.. and Beahrs, 0. H.. J. C/in. Endotrino!. 19, 53, 1959. Hirabayashi, R. N., and Lindsay, S., In “International Colloquium on Tumors of the Thyroid Gland”, Marseille, 1964. (A. Appaix. Ed.), pp. 292-298, American Elsevier, New York. 1966. Goudie, R. B., ln “International Colloquium on Tumors of the Thyroid Gland”, Marseille, 1964, (A. Appaix, Ed.), pp. 272-291, American Elsevier, New York, 1966. Weigle, W. O., In “Pathology Annual,” (S. C. Sommers, Ed), pp. 329-347, Appleton Century Crofts, New York, 1973. Weigle. W. O., and Nakamura, R. M., C/in. Exp. Imm~nol. 4, 645, 1969. Koffler. D., and Friedman, A. H., Lab. Inrj~sr. 13, 239, 1964. Cochrane, C. G., J. Exp. Med. 134, 75s, 1971. Pierce, G. B., Beals, T. F., Ram, J. S., and Midgley, A. R., Amer. J. Patho/. 45, 929, 1964. Pierce, G. B. Midgley, A. R., and Ram, J. S., J. Exp. Med. 117, 339, 1963. Pierce, G. B., and Nakane, P. K., Lab. Invest. 17, 499, 1967. Lever, J. D., J. Biophys. Biochem. Cytol. 2, 293, 1956. Pierce, G. B., Nakane, P. K.. Lab. Invest. 21, 27, 1969. Delepesse, G., Duchateau, J., Collet, H., Govaersts, A., and Bastenie, P. A., C/in. Exp. Immunol. 12, 439, 1972. Lamki, L., Row, W., and Volpe, R., J. C/in. Endou;not. Metab. 37, 358, 1973.