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Silent thyroiditis: A histologic and immunohistochemical study
Silent Thyroiditis: A Histologic and Immunohistochemical Study YUJI MIZUKAMI, MD,* TAKATOSHI MICHIGISHI,MD,t TAKUMA HASHIMOTO, MD,* NORIHISATONAMI, MD,* KINICHI HISADA,MD,t FUJITSUGU MATSUBARA,MD,* AND EISUKETAKAZAKURA,MD* Twenty-six specimens obtained from 23 patients with clinically and laboratory-proven silent thyroiditis were examined histologically; 11 specimens were obtained during the thyrotoxic phase, and 15 specimens during the early or late recovery phase. All specimens showed chronic thyroiditis, focal or diffuse type; and lymphoid follicles were present in about half of the specimens. Most specimens showed neither stromal fibrosis nor oxyphilic cell changes. The follicular disruptions, which varied from moderate to severe and involved nearly all the visible follicles, were characteristic and common histologic features of this disorder. Giant cells were present in about two thirds of specimens. Six of the 7 specimens taken during the late recovery phase showed no follicular disruption. In 3 patients who had follow-up biopsies, the histologic involvement in the initial biopsy specimens clearly had disappeared in the second biopsy specimens. These histologic features indicate that silent thyroiditis may be a form of chronic thyroiditis, i.e., "chronic thyroiditis with marked follicular destruction." Thyroid biopsy is recommended as a useful tool in differentiating this disease from other thyroid diseases causing hyperthyroidism. In addition to the histologic analysis, intrathyroidal lymphocyte subsets were examined immunohistochemically and compared to those in chronic thyroiditis (Hashimoto's thyroiditis). In both silent and chronic thyroiditis, a great majority of lymphocytes infiltrating between thyroid follicles showed a T-cell phenotype, and no significant differences in Tcell and B-cell distribution between the diseases were observed. HUM PATHOL19:423--431, 1988. 9 1988 by W,B. Saunders Company.
clarified. Histologic studies, however, are scarce, being limited to only 30 reported cases. 5-7 Although silent thyroiditis has been claimed to share most of the histologic features of chronic thyroiditis, some questions concerning its histologic features remain unanswered. In the present report, 26 thyroid biopsy specimens obtained from 23 patients with silent thyroiditis were examined to determine the histologic findings c o m m o n to and characteristic of the disease. We also attempted to investigate the immunopathologic mechanism in silent thyroiditis by determining the relative numbers of T and B lymphocytes in the thyroid infiltrates. MATERIALSAND METHODS
Silent thyroiditis 1'2 is a transient form of hyperthyroidism characterized by a painless, nontender thyroid gland, elevated blood levels of thyroxine (T4) and triiodothyronine (T3), a low radioactive iodine uptake, and spontaneously resolving hyperthyroidism. This disease is also called painless thyroiditis? '4 t r a n s i e n t h y p e r t h y r o i d i s m with l y m p h o c y t i c thyroiditis, 5 atypical subacute thyroiditis, 1 lymphocytic t h y r o i d i t i s with s p o n t a n e o u s l y r e s o l v i n g hyperthyroidism, 6 or chronic lymphocytic thyroiditis, thyrotoxicosis, and low radioactive iodine uptake. 7 Many studies of this disease have been reported, and its clinical and laboratory characteristics have been From the *Central Clinical Laboratory and ?Department of Nuclear Medicine, Kanazawa University Hospital Takara-machi, Kanazawa, and ~Kurobe Citizen Hospital, Kanaya, Kurobe, Japan. Revision accepted for publication 28 June 1987. Address correspondence and reprint requests to Dr. Mizukami: Central Clinical Laboratory, Kanazawa University Hospital, 13-1, Takara-machi, Kanazawa, Japan. Keywords: chronic thyroiditis, follicular disruption, immunohistochemistry, intrathyroidal B cells, intrathyroidal T cells, silent thyroiditis. 9 1988 by W.B. Saunders Company. 0046-8177/88 $0.00 + .25
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Twenty-three patients from Kanazawa University Hospital and Kurobe Citizen Hospital between 1980 and 1986 were included in this study. All patients showed typical clinical and laboratory features of silent thyroiditis: high serum values of T 4 and T 3, low values of radioactive iodine uptake, painless goiter, and spontaneously resolving hyperthyroidism. All patients had received no treatment until the time of biopsy. A percutaneous needle biopsy (Silverman) of the thyroid was p e r f o r m e d during the thyrotoxic phase or after recovery. T h e clinically and laboratoryproven recovery phase was divided into early recovery phase and late recovery phase in our study because of a histologic similarity between the thyrotoxic phase and the early recovery phase and a difference between the early recovery phase and the late recovery phase. In most cases, the early recovery phase was within about 4 weeks after the resolution of hyperthyroidism. Twenty-six specimens were obtained by single or multiple needle biopsies from 23 patients. Eleven specimens were obtained during the thyrotoxic phase, 8 during the early recovery phase, and 7 during the late recovery phase. In 3 patients, having biopsies during the thyrotoxic phase, the thyroid biopsy was repeated during the late recovery phase. Serum levels of T4, T3, free T4, free T 3, and thyrotropin were determined by radioimmunoassay. T h e normal levels were as follows: T4, 4.6 to 11.0 txg/dL; T3, 95 to 200 ng/dL; free Y4, 0.7 to 2.1 ng/dL; free T 3, 2.3 to 5.4 pg/mL; and thyrotropin, <10 p.U/mL. Thyroid antibodies in serum were examined by the thyroglobulin-coated and microsome-coated tanned erythrocyte hemagglutination tests. T h e normal range of thyroid antibody levels was <1:100. Three-hour and 24-hour thyroid uptake of iodine-
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123 was measured by a standard technique. The normal range was 7 to 35% (3 hour) and 10 to 40% (24 hour).
lin-eosin-stained sections whose identifying numbers had been masked. The histologic diagnosis of thyroiditis was based on criteria by Woolner et al. s Severity of thyroiditis was graded in terms of replacement by lymphocytic infiltrates or interstitial fibrosis. The variety of follicular epithelial changes was also graded in terms of degree of replacement by each follicular epithelial change. Diffuse thyroiditis implies an interfollicular lymphocytic infiltration that was complete or virtually so. Focal thyroiditis implies focal or spotty collection of lymphocytes with or without a
Histologic Examination
The thyroid specimens were fixed with buffered neutral formalin, and the sections were processed in a routine manner and stained with hematoxylin-eosin. Histologic appearances were estimated independently by two observers (YM and FM) on hematoxyTABLE t.
Case No.
Date of A g e (yrs)/ E x a m i Sex nation
1
24/F
2
34/F
3
47/F
4
28/F
5
34/F
6
36/F
10/80 3/81 11/80 5/81 8/82 1/83 7/83 8/83 10/83 11/83 10/84
15/F
8
33/F
9
62/F
10
45/F
11
15/F
12
36/F
13
33/F
14
17/F
15
48/M
16
43/F
17
20/F
18
46/F
19
54/F
20
47/F
21
40/F
22
30/F
23
48/F
Normal range
-
Free T 4 Ts Free T 3 TSH (ng/dL) (ng/dL) (pg/mL) (IxU/mL)
14.4 6.6 13.4 28.2 7.3 25.4 6.7 12.0 11.0 16.1
2.3 1.7 -
346 116 316 93 252 121 550 106 216 168 192
. -
-
1.4
89
-
9/84 10/84 6/84 11/84 7/84 8/84 10/84 11/84 11/84 7/85 8/85 10/85 12/85 1/86 12/85 2/86 5/85 6/85 1/86 2/86 1/86 3/86 2/86 3/86 2/86 3/86 5/86 6/86 5/86 9/86 7/86 8/86 7/86 9/86
14.3 12.8 17.2 10.0 11.6 5.1 7.3 12.1 -
3.6 0.7 3.7 1.1 3.0 2.2 3.1 1.1 2.2 1.4 2.6 1.3 7.9 1.7 3.4 1.2 3.1 1.2 6.4 1.3 2.3 2.8 2.8 0.7 3.8 2.1 2.7 0.6 4.4 1.2 9.1 4.3 4.2 0.6
224 115 217 121 233 180 198 109 185 156 128 104 295 128 256 103 338 113 157 176 195 91 114 154 70 119 242 85
17.4 4.4 8.2 5.4 7.3 3.1 7.6 4.7 10.6 15.9 8.7 -
-
4.6-11.0
0.7-2.1
95-200
2.3-5.4
11/84
7
T4 (p,g/dL)
Laboratory Data on 23 Patients with Silent Thyroiditis
3 6 <2 5 <2 5 <2 .
R A I U (%)
ESR (mm)
3h
24 h
1h 2 h
2.8 32.1 2.5 . -* . 0.7
1.8 55.3 1.9 . . 0.1
. <2 <2 <2 <2
<2 6 <2 3 <2 <2 <2 <2 <2 <2 <2 <0.2 <0.2 <0.2 9 <2 <2 <0.2 <0.2 <0.2 <2 <2 35 <0.2 <0.2 <2.0 19 <0.2 1.2 <0.2 <0.2 <2 7 <10
. 2.8 . 1.6 . 1.4 . 3.3 . 3.4 . 2.2 . 2.8 2.8 . 1.7 . 1.9 27.9 2.1 1.9 2.1 2.2 3.3 . 3.1 . 1.6 . 4.4 . 2.1 2.5 . 1.6 .
1.1 . 0.2 . 0.3 . 0.8 . 0.9 . 0.3 . 3.0 0.7 . 0.6 . 0.6 68.0 0.7 1.0 0.3 0.7 3.5 . 2.9 . 0.7 . 6.0 . 0.9 1.5 . 0.3 .
7-35
10~t0
MCHA Titer 202 402
8 23 802 . . 5 18 < 1 0 2 . . 16 4 0 <102 . . 11 29 <102 . . 9 28 402 . . 15 33 802 . . 7 11 402 . . 47 94 l02 . . 11 33 802 . . 36 71 202 202 402 . . 802 . . 802 <102 9 24 <102 1602 . . 16 4 0 202 . . <102 . . 802 . . <102 < 102 . . 11 34 402 . . <102
Date of Biopsy
Functional Phase at Time of Biopsy
202 202 1602
3/81
Late recovery
5/81
Late recovery
<102 <102
8/82 1/83 8/83
Thyrotoxic Late recovery Early recovery
<102
11/83
Early recovery
<102
10/84
Thyrotoxic
202
10/84
Early recovery
102 <102
1/84 11/84 8/84
Thyrotoxic Late recovery Thyrotoxic
202
11/84
Early recovery
202 102 802
7/85
Late recovery
10/85
Late recovery
<102
1/86
Early recovery
<102 <102 <102 402
2/86
Early recovery
5/85
Thyrotoxic
2/86
Thyrotoxic
3/86
Thyrotoxic
202
3/86
Early recovery
<102
3/86
Thyrotoxic
802
6/86
Early recovery
<102 < 102 -
5/86 9/86 8/86
Thyrotoxic Late recovery Thyrotoxic
<102
7/86
Thyrotoxic
TGHA Titer
<102
-
-
ABBREVIATIONS: T4, t h y r o x i n e ; T 3, t r i i o d o t h y r o n i n e ; T S H , t h y r o t r o p i n ; R A I U , r a d i o a c t i v e i o d i n e u p t a k e ; ESR, e r y t h r o c y t e s e d i m e n tation rate; TGHA, thyroglobulin-coated tanned erythrocyte hemagglutination; MCHA, microsome-coated tanned erythrocyte hemagglutination. * T h y r o i d was not visualized on the scan with 9 9 m T c O 4 - .
424
SILENTTHYROIDITIS[Mizukami et al.] TABLE 2. Histological Observations on 26 Biopsy Specimens Obtained During Thyrotoxic, Early Recovery, and Late Recovery Phases of Silent Thyroiditis
Histologic Characteristics Pattern of infiltration D e g r e e o f infiltration in focal thyroiditis Hyperplastic follicles
Oxyphilic c h a n g e s
Fibrosis
Follicular d e s t r u c t i o n
Grade
% Replacement
Thyrotoxic Phase
Early Recovery Phase
Late Recovery Phase
5 6 3 0 2 1 3 5 2 6 3 1 1 8 3 0 0 0 2 4 5 7 4 9 2
4 4 1 2 1 1 1 2 4 5 1 1 1 5 2 1 0 0 3 2 3 4 4 4 4
7 0 6 1 0 4 2 1 0 6 1 0 0 5 2 0 0 6 1 0 0 4 3 0 7
Focal Diffuse 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3
L y m p h o i d follicles Giant cells
1-25 26-50 51-100 0 1-25 26-50 51-100 0 1-25 26-50 51-100 0 1-25 26-50 51-100 0 1-25 26-5O 51-100 Present Absent Present Absent
formation of germinal follicles. In focal thyroiditis, the degree of cell infiltration was graded from 1 to 3. Grade 1 indicates less than 25% loss of parenchyma by scattered collections of lymphocytes, grade 2 indicates from 26 to 50% replacement by infiltration, and grade 3 indicates greater than 51% replacement. Hyperplasticfollicle implies cuboidal or slightly columnar epithelium with some irregularity in shape of the follicle or some degree of papillary folding. Oxyphilic change implies swollen, oxyphilic, and granular changes of follicular epitheli. Follicular destruction implies breakdown of follicles with infiltration of degenerated and desquamated epithelium into the follicle and heavy aggregation of lymphocytes around the follicle. The degree of each epithelial and follicular change was also graded from 0 to 3. Grade 0 indicates no replacement of parenchyma, grade 1 indicates 1 to 25% replacement, grade 2 indicates 26 to 50% replacement, and grade 3 indicates greater than 51% replacement. Immunohistochemical Examination
The 26 specimens of thyroid with silent thyroiditis and, for comparison, 20 specimens of thyroid with chronic thyroiditis (16 cases of diffuse thyroiditis and 4 of focal thyroiditis) were examined immunohistochemically for the distribution of T and B lymphocytes infiltrating the thyroid tissues. Control tissues comprised two lymph nodes with nonspecific follicular hyperplasia. For immunohistochemical study, sections of par-
affin-embedded tissue were stained with monoclonal antibodies to T (MT-I) or B lymphocytes (MB-I) (BioScience Products, Emmenbrficke, Switzerland). Both antibodies were used in 1:20 dilution. Both antibodies react in formalin-fixed, paraffin-embedded sections, according to the manufacturer. All sections were stained by the avidin-biotin-peroxidase complex (ABC) method. Briefly, the tissue sections were deparaffinized in xylene and immersed in methanol containing 0.3% hydrogen peroxide for 30 minutes at room temperature. The sections were overlaid with the respective antibody for 30 minutes. After rinses in phosphate-buffered saline, the procedure was continued with conventional ABC reagents (Vector Laboratories, Burlingame, CA). Finally, the slides were immersed in 3,3'-diaminobenzidine solution (0.25 rag/ mL with 0.03% hydrogen peroxide) and counterstained with methyl green. Control sections of lymph nodes were included with each examination and revealed localization of monoclonal antibodies to T-cell and B-cell areas. Negative control specimens were prepared by substitution of phosphate-buffered saline for the primary antiserum. RESULTS Clinical a n d Laboraton/Findings
Table 1 shows the results of the clinical and laboratory assessment of the 23 patients. All patients presented with asymptomatic goiter with normal or somewhat firm consistency. Twenty-two patients were female and 1 was male. The average age at pre425
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sentation was 36.3 -+ 12.7 years. Eight patients (cases 1, 2, 4, 8, 15, 16, 22, and 23) had symptoms of hyperthyroidism of a mild to moderate degree. The other 15 patients had no symptoms of hyperthyroidism and only elevated serum levels of T 3, Y4, o r free T 4. None of the patients complained of pain or tenderness over the thyroid area. The radioactive iodine uptake was measured in 22 patients and was less than 6.0% (24 hour) in all of them. The serum levels of T4, T 3, free T4, o r free T 3 were elevated mildly to moderately. The erythrocyte sedimentation rate was determined in 13 patients and was normal or mildly elevated (< 16 ram/h), except in 2 patients. The serum thyroglobulin titers were elevated in 10 patients, and the serum microsome titers were elevated in 15 patients; however, both titers were relatively low. A transient hypothyroidism was observed in 7 patients
(cases 6, 7, 9, 10, 18, 20, and 21). Two patients (cases 4 and 13) were in the postpartum period. Histologic Findings
Table 2 shows the results of histologic evaluation of 26 biopsy specimens. Lymphocyte infiltration, which varied from minimal to severe, was present in all specimens. The histologic patterns of 11 samples from the toxic phase and those of 8 samples from the early recovery phase were essentially similar and characteristic of this disease. On the other hand, 7 samples from the late recovery phase showed only a pattern of chronic focal thyroiditis with normal follicular architecture. Therefore, the results of the quantitative histologic analysis are described separately.
FIGURE 1 [top). Thyrotoxic phase. A, Case 16. Diffuse infiltration of lymphocytes is observed. Many follicles are disrupted, and giant cells are found within the follicles. There is no evidence of granulomatous lesions of subacute thyroiditis. B, Case 22. Focal infiltration of lymphocytes is observed. Follicles are disrupted, and many macrophages or desquamated follicular cells are contained within the follicles. Oxyphilic epithelial changes are not evident. [Both, x100.] FIGURE 2 [bottom]. Earlyrecovery phase. A, Case 4. Diffuse infiltration of lymphocytes is observed. Marked follicular disruption and lack of oxyphilic epithelium are prominent histologic features, similar to those in the thyrotoxic phase. B. Case 10. The findings are similar to those shown in panel A [Both, x100.]
426
SILENT THYROIDITIS [Mizukami et al.]
. ~
k ",~;
N 7-
FIGURE 3. Late recovery phase. ~ Case 2. Only focal infiltration of lymphocytes is observed. Most of the follicles are intact, but some variation in follicle size is observed. There is no evidence of follicular disruption. B, Case 11. The findings are similar to those shown in panel A, Focal lymphocytic infiltration and slightly larger follicles with a low cuboidal follicular epithelium are observed. [ Both, x40.]
Specimens in Thyrotoxic Phase and in Early Recovery Phase. The number of specimens with focal thyroiditis or diffuse thyroiditis was nearly equal. In the samples of focal thyroiditis, two thirds of the samples showed up to 50% replacement by lymphocyte infiltration. Hyperplastic follicular changes varied greatly with the sample, but the degree was generally greater in the early recovery phase than in the thyrotoxic phase. Oxyphilic changes were absent in 11 of the 19 samples, and 4 showed up to 25% replacement by oxyphilic cell changes; however, the remaining 4 were greater than 26%. Over two thirds of the specimens showed no or minimal fibrosis, and marked fibrosis with severe parenchymal replacement was not observed. Follicular destruction, which characterizes this disease, was observed exclusively in all specimens. The degree of follicular destruction varied greatly in the specimens: 5 showed less than 25% replacement, 6 showed 26 to 50% replacement, and 8 showed greater than 51% replacement. Lymphoid follicles were present in about half the specimens. Giant cells within or around the disrupted follicles were seen in two thirds of the specimens, but typical granulomatous lesions of subacute thyroiditis were not observed in the specimens (fig. I, thyrotoxic phase; fig. 2, early recovery phase). Specimens in Late Recovery Phase. All seven specimens showed focal thyroiditis.The degree of lymphocyte infiltration was minimal or mild, with less than 25% replacement by lymphocyte infiltration. Lymphoid follicles were present in four specimens. The follicular architecture was well preserved and similar to that in the normal thyroid. Follicular destruction, oxyphilic cell changes, and fibrosis were never observed in the specimens (fig. 3, late recovery phase). Follow-up Biopsy Study. Three of the 23 patients had follow-up biopsies done. The first biopsy speci-
men was obtained in the thyrotoxic phase, and the second biopsy specimen was from the late recovery phase, although the period between the first and second biopsies varied. The first biopsy specimens from the toxic phase showed marked follicular destruction and various epithelial changes except epithelial oxyphilia. On the other hand, the second biopsy specimens from the late recovery phase showed only minimal to mild lymphocyte infiltration and normal follicular structure, indicating improvement of histologic features (figs. 4 to 6).
Immunohistochemical Findings Results in control lymph nodes were similar to those obtained previously with monoclonal antibodies of the OKT series. T cells were concentrated in the paracortex, and a small percentage (mean, 20%) were present within germinal centers (fig. 7A). Most germinal centers and cells in the mantle zone stained predominantly with B-cell antiserum (fig. 7B). In both silent thyroiditis and chronic thyroiditis, the 1.ymphocytes formed lymphofollicles in the thyroid nssues and showed a similar distribution of T and B cells to that of control lymph nodes (fig. 7C). T cells were predominantly distributed in the paracortical areas, and B cells were in the germinal centers and mantle zones. In both silent thyroiditis and chronic thyroiditis, a great majority of the lymphocytes infiltrating between thyroid follicles (>99%) showed a T~ cell phenotype (figs. 7D and E). Very few scattered cells showed a B-cell phenotype. No significant differences in distribution of T and B cells were found between silent thyroiditis and chronic thyroiditis. In cases of silent thyroiditis, many T lymphocytes were aggregated around the disrupted thyroid follicles, and some T lymphocytes were also infiltrated within the intrafollicular spaces (fig. 7F). 427
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428
SILENTTHYROIDITIS[Mizukami et aL] FIGURE 4 [top], Case 3. The first biopsy during thyrotoxic phase [left]. Many giant cells are formed within a follicle, and other follicles are not involved. This appearance closely resembles that of early-phase subacute thyroiditis, causing difficulty in differentiating silent thyroiditis from subacute thyroiditis in this case. [• The second biopsy during late recovery phase [right] shows the thyroid is nearly normal. Ix40.] FIGURE 5 [middle], Case 8, The first biopsy during thyrotoxic phase [left] shows marked follicular destruction and diffuse lymphocytic infiltration, characteristic to silent thyroiditis. [x100]. The second biopsy during late recovery phase [right] shows that the degree of follicular destTuction is markedly decreased and the thyroid is almost normal. [• FIGURE 6 [bottom], Case 21, The first biopsy during thyrotoxic phase [left] and the second biopsy during late recovery phase [right]. The findings are similar to those in Case 8 [fig. 5]. An improvement in histologic features is observed, [left,, x 100; right x40.]
DISCUSSION
Thyrotoxicosis with low radioactive iodine uptake is usually associated with subacute thyroiditis or ingestion of exogenous thyroid hormone. Subacute thyroiditis is characterized by transient thyrotoxicosis, painful and tender goiter, fever, elevated erythrocyte sedimentation rate, and low radioactive iodine uptake. Several reports of patients with silent thyroiditis have been published since 1975.1-s This disease is a transient form of thyrotoxicosis characterized by painless, nontender goiter and a low radioactive iodine uptake and differs from subacute thyroiditis in its higher frequency of antithyroid antibodies, absence of the very high erythrocyte sedimentation rate, and absence of pain and tenderness. Histologically, silent thyroiditis shows a pattern with consistent chronic thyroiditis; giant cell granuloma, which is characteristic of subacute thyroiditis, is not observed. Nikolai et al. 6 described the histologic findings of biopsy specimens from 12 patients with silent thyroiditis as m o d e r a t e - f o c a l or diffuselymphocytic infiltration, follicular disruption, occasional oxyphilic changes, minimal or no fibrosis, and no germinal centers. Gorman et al. 5 reported 4 cases of silent thyroiditis, showing lymphocytic infiltration and extensive follicular destruction without oxyphilia. No case of subacute thyroiditis was seen in either study. In the present study, we reviewed 26 specimens from 23 patients. The histologic features were essentially consistent with chronic lymphocytic thyroiditis. The most cogent differences in histologic features of silent thyroiditis were a pronounced follicular destruction and a lack of oxyphilic changes, as pointed out by Gorman et al. 5 Such an extensive follicular destruction is not seen in ordinary chronic thyroiditis, and this finding seems to be useful in differentiating silent thyroiditis from other forms of thyroiditis. This extensive follicular destruction also indicates that the thyrotoxic state in silent thyroiditis results from release of stored hormone into the circulation following follicular destruction, just as in subacute thyroiditis. It has been shown that follicular d e s t r u c t i o n is also seen in c h r o n i c " j u v e n i l e " thyroiditis 9 and palpation thyroiditis. 1~ In both diseases, however, follicular destruction is more sporadic and sparse than in silent thyroiditis, and thyrotoxicosis is usually not associated. Chronic thyroiditis presenting with thyrotoxicosis has been known and is sometimes encountered in the clinic. This disorder is characterized by nontender painless thyroid, elevated levels of T 4 and T 3, 429
and elevated uptake of radioactive iodine. This disorder is the so-called hashitoxicosis. 11 Hashitoxicosis usually requires treatment with antithyroid drugs to terminate hyperthyroidism. On the other hand, silent thyroiditis is self-limiting and does not require therapy for hyperthyroidism. Histologically, hashitoxicosis shows combined features of Graves' disease and chronic thyroiditis, with no or minimal follicular destruction. Therefore, thyroid biopsy seems to be useful in distinguishing silent thyroiditis from hashitoxicosis. Inada et a1.12 reported that histologic abnormalities, such as lymphocytic infiltration and follicular epithelial changes, were alleviated spontaneously within several months in two patients with silent thyroiditis. In the present study, follow-up biopsies were p e r f o r m e d in three patients. Each second biopsy specimen showed only mild lymphocytic infiltration and no evidence of follicular destruction. This finding indicates not only recovery of clinical and laboratory findings but also recovery of histologic features in the course of silent thyroiditis. Postpartum thyroiditis, which is characterized by a reversible thyrotoxic or hypothyroid phase during the y e a r a f t e r c h i l d b i r t h , has also b e e n recognized.I3'~4 The histologic features of the thyroid in this condition have been obscure. Inada et al. 15 reported one case of postpartum thyroiditis in which the histologic appearance of the thyroid was similar to that in silent thyroiditis. In our study, two patients were in a postpartum period, and the histologic features of their thyroid glands were similar to those in other patients with silent thyroiditis, i.e., diffuse or focal lymphocytic infiltration and marked follicular destruction. This result suggests that both silent thyroiditis and postpartum thyroiditis can be fitted into the same category, and a similar factor may induce both thyroiditides. The pathogenesis of silent thyroiditis is not clear9 Morrison and Caplan 1 reported one case of typical subacute thyroiditis and one of silent thyroiditis in a wife and husband and suggested that silent thyroiditis is in the range of subacute thyroiditis (atypical subacute thyroiditis). Nikolai et al. ~ investigated the viral antibody response for a range of viruses in this disease, but no definite evidence for a viral etiology was 9 obtained. On the other hand, Amino et al. l o suggested that autoimmunity plays an important role in the pathogenesis of silent thyroiditis as well as in H a s h i m o t o ' s d i s e a s e , a n d at p r e s e n t , m a n y investigators 17-2~ believe that this disease is due to enhancement of i m m u n e activity9 Jansson et al. 19
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SILENT THYROIDITIS [Mizukami et al.] FIGURE 7. A, Control lymph node stained with MT-I for T cells. MT I + lymphocytes are concentrated in the paracortex area. Some are also present in the germinal center and follicular mantle. B, Control lymph node stained with MB-I for B cells. MB-I + lymphocytes are predominantly distributed in the mantle and germinal centers. C, Thyroid with chronic thyroiditis stained with MB-I. Only lymphocytes in the follicular mantle are positive. Lymphocytes scattered between thyroid follicles are negative. D, Thyroid with chronic thyroiditis stained with MT-I.A great majority of infiltrating lymphocytes are positive for MT-I, E, Thyroid with silent thyroiditis stained with MT-I. All lymphocytes infiltrating between thyroid follicles are positive for MT-I. F. Thyroid with silent thyroiditis stained with MT-I. A dense accumulation of MT-I + lymphocytes is observed around the disrupted follicle. Some MT-I § lymphocytes are also observed within the follicular lumen. JAil, methyl green counterstains, A, D, E, and F, x200; B and C, xfl00.]
Acknowledgments. T h e a u t h o r s t h a n k Dr. M. Kawato for critical c o m m e n t s a n d Sanae Itoh for h e r assistance in the p r e p a r a t i o n of the m a n u s c r i p t .
showed a relative accumulation of B cells and a relative decrease of suppressor-cytotoxic T cells in the thyroid tissues of this disease. Elliot et al. 2~ also reported a predominant infiltration of T cells, especially helper-inducer T cells, in the thyroid tissues in this disease. These studies on local lymphocyte subsets suggest the importance of local autoantibody production in the pathogenesis of this disease. In the present immunohistochemical study, a great majority of the infiltrating lymphocytes were T cells, and no differences in distribution of T and B cells were observed as compared to that in chronic thyroiditis. No evidence of accumulation of B cells was found, in contrast to the report ofJansson et al. 19 The monoclonal antibody against T cells used in this study is unable to distinguish suppressor-cytotoxic T cells from helper-inducer T cells. Therefore, we were unable to determine a relative distribution of each T-cell subset. We presume that thyrotoxicosis in this disease results from destruction of thyroid follicles. Therefore, it is of interest whether follicular destruction is caused by a cytotoxic effect of infiltrating T cells. We would like to assume that the inflammatory process of this disease is extremely rapid and thyroid follicles are easily destroyed by the cytotoxic effects of the infiltrating T lymphocytes. We are attempting to quantify intrathyroidal T-cell subsets using the monoclonal antibody O K T series. The absence of oxyphilic cell changes or stromal fibrosis, which is also a histologic feature characteristic of this disease, is probably due to the rapid progression of inflammation in this disease. Woolner et al. 8 classified chronic thyroiditis into focal thyroiditis and diffuse thyroiditis and further divided diffuse thyroiditis into four subtypes on the basis of epithelial changes, stromal fibrosis, and cell infiltration. Woolner and colleagues' classification of chronic thyroiditis has been the one used most frequently by pathologists, because for each subtype, the histologic appearances and functional effects are consistent. However, a description concerning chronic thyroiditis associated with such an extensive follicular destruction could not be found in this classification. We found that silent thyroiditis is essentially in the entity of chronic thyroiditis and that the extensive follicular disruption is the differential diagnostic point in assessment of silent thyroiditis. The thyrotoxicosis in this disease is transient and self-limited, and usually treatment is unnecessary. Therefore, this disease should be differentiated from other forms of thyroiditis, such as subacute thyroiditis, Graves' disease, or hashitoxicosis. We would like to refer to this disease as "chronic thyroiditis with marked follicular destruction" from the standpoint of pathologists.
REFERENCES 1. Morrison J, Caplan RH: Typical and atypical "silent" subacute thyroiditis in a wife and husband. Arch Intern Med 138:45, 1977 2. Papapetrou PD, Jackson IMD: Thyrotoxicosis due to "silent" thyroiditis. Lancet 1:361, 1975 3. Dorfman SD, Cooperman MT, Nelson RL, et al: Painless thyroiditis and transient hyperthyroidism without goiter. Ann Intern Med 86:24, 1977 4. Woolf PD, Daly R: Thyrotoxicosis with painless thyroiditis. Am J Med 60:73, 1976 5. Gorman CA, Duick DS, Woolner LB, et al: Transient hyperthyroidism in patients with lymphocytic thyroiditis. Mayo Clin Proc 53:359, 1978 6. Nikolai TF, Brosseau J, Kettrick MA, et al: Lymphocytic thyroiditis with spontaneously resolving hyperthyroidism (silent thyroiditis). Arch Intern Med 140:478, 1980 7. Gluck FB, Nusynowitz ML, Plymate S: Chronic lymphocytic thyroiditis, thyrotoxicosis, and low radioactive iodine uptake. N EnglJ Med 293:624, 1975 8. Woolner LB, McConahey W, Beahrs OH: Struma lymphomatosa (Hashimoto's thyroiditis) and related thyroidal disorders. J Clin Endocrinol 19:53, 1959 9. Sato T, Takata I, Taketani T, et al: Concurrence of Grave's disease and Hashimoto's thyroiditis. Arch Dis Child 52:951, 1977 10. Carney JA, Moore SB, Northcutt RC, et al: Palpation thyroiditis (multifocal granulomatous folliculitis) Am J Clin Pathol 64:639, 1975 11. Means JH, DeGroot LJ, Standbury JB: The Thyroid and Its Diseases, ed 3. New York, McGraw-Hill, 1963 12. Inada M, Nishikawa M, Naito K, et al: Reversible changes of the histological abnormalities of the thyroid in patients with painless thyroiditis. J Clin Endocrinol Metab 52:431, 1981 13. Amino N, Miyai K, Onishi T, et al: Transient hypothyroidism after delivery in autoimmune thyroiditis. J Clin Endocrinol Metab 42:296, 1976 14. Ginsburg J, Walfish PG: Postpartum transient thyrotoxicosis with painless thyroiditis. Lancet 1:1125, 1977 15. Inada M, Nishikawa M, Oishi M, et al: Postpartum transient thyrotoxicosis: report of two cases. Endocrinol Jpn 26:611, 1979 16. Amino N, Mori H, Iwatani Y, et al: High prevalence of transient postpartum thyrotoxicosis and hypothyroidism. N EnglJ Med 306:849, 1982 17. Farid NR, Hawa BS, Walfish PG: Increased frequency of HLA-DR3 and 5 in the syndromes of painless thyroiditis with transient thyrotoxicosis: evidence for an autoimmune etiology. Clin Endocrinol 19:699, 1983 18. Jansson R, Bernander S, Karlsson A, et al: Autoimmune thyroid dysfunction in the postpartum period. J Clin Endocrinol Metab 58:681, 1984 19. Jansson R, T6tterman TH, Sallstrom J, et al: Intrathyroidal and circulating lymphocyte subsets in different stages of autoimmune postpartum thyroiditis. J Clin Endocrinol Metab 58:942, 1984 20. Elliot I, Gupta M, Hostetter A, et al: Immunologic studies in two patients with persistent lymphocytic thyroiditis, thyrotoxicosis, and low radioactive iodine uptake. Am J Med 77:347, 1984
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clarified. Histologic studies, however, are scarce, being limited to only 30 reported cases. 5-7 Although silent thyroiditis has been claimed to share most of the histologic features of chronic thyroiditis, some questions concerning its histologic features remain unanswered. In the present report, 26 thyroid biopsy specimens obtained from 23 patients with silent thyroiditis were examined to determine the histologic findings c o m m o n to and characteristic of the disease. We also attempted to investigate the immunopathologic mechanism in silent thyroiditis by determining the relative numbers of T and B lymphocytes in the thyroid infiltrates. MATERIALSAND METHODS
Silent thyroiditis 1'2 is a transient form of hyperthyroidism characterized by a painless, nontender thyroid gland, elevated blood levels of thyroxine (T4) and triiodothyronine (T3), a low radioactive iodine uptake, and spontaneously resolving hyperthyroidism. This disease is also called painless thyroiditis? '4 t r a n s i e n t h y p e r t h y r o i d i s m with l y m p h o c y t i c thyroiditis, 5 atypical subacute thyroiditis, 1 lymphocytic t h y r o i d i t i s with s p o n t a n e o u s l y r e s o l v i n g hyperthyroidism, 6 or chronic lymphocytic thyroiditis, thyrotoxicosis, and low radioactive iodine uptake. 7 Many studies of this disease have been reported, and its clinical and laboratory characteristics have been From the *Central Clinical Laboratory and ?Department of Nuclear Medicine, Kanazawa University Hospital Takara-machi, Kanazawa, and ~Kurobe Citizen Hospital, Kanaya, Kurobe, Japan. Revision accepted for publication 28 June 1987. Address correspondence and reprint requests to Dr. Mizukami: Central Clinical Laboratory, Kanazawa University Hospital, 13-1, Takara-machi, Kanazawa, Japan. Keywords: chronic thyroiditis, follicular disruption, immunohistochemistry, intrathyroidal B cells, intrathyroidal T cells, silent thyroiditis. 9 1988 by W.B. Saunders Company. 0046-8177/88 $0.00 + .25
423
Twenty-three patients from Kanazawa University Hospital and Kurobe Citizen Hospital between 1980 and 1986 were included in this study. All patients showed typical clinical and laboratory features of silent thyroiditis: high serum values of T 4 and T 3, low values of radioactive iodine uptake, painless goiter, and spontaneously resolving hyperthyroidism. All patients had received no treatment until the time of biopsy. A percutaneous needle biopsy (Silverman) of the thyroid was p e r f o r m e d during the thyrotoxic phase or after recovery. T h e clinically and laboratoryproven recovery phase was divided into early recovery phase and late recovery phase in our study because of a histologic similarity between the thyrotoxic phase and the early recovery phase and a difference between the early recovery phase and the late recovery phase. In most cases, the early recovery phase was within about 4 weeks after the resolution of hyperthyroidism. Twenty-six specimens were obtained by single or multiple needle biopsies from 23 patients. Eleven specimens were obtained during the thyrotoxic phase, 8 during the early recovery phase, and 7 during the late recovery phase. In 3 patients, having biopsies during the thyrotoxic phase, the thyroid biopsy was repeated during the late recovery phase. Serum levels of T4, T3, free T4, free T 3, and thyrotropin were determined by radioimmunoassay. T h e normal levels were as follows: T4, 4.6 to 11.0 txg/dL; T3, 95 to 200 ng/dL; free Y4, 0.7 to 2.1 ng/dL; free T 3, 2.3 to 5.4 pg/mL; and thyrotropin, <10 p.U/mL. Thyroid antibodies in serum were examined by the thyroglobulin-coated and microsome-coated tanned erythrocyte hemagglutination tests. T h e normal range of thyroid antibody levels was <1:100. Three-hour and 24-hour thyroid uptake of iodine-
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123 was measured by a standard technique. The normal range was 7 to 35% (3 hour) and 10 to 40% (24 hour).
lin-eosin-stained sections whose identifying numbers had been masked. The histologic diagnosis of thyroiditis was based on criteria by Woolner et al. s Severity of thyroiditis was graded in terms of replacement by lymphocytic infiltrates or interstitial fibrosis. The variety of follicular epithelial changes was also graded in terms of degree of replacement by each follicular epithelial change. Diffuse thyroiditis implies an interfollicular lymphocytic infiltration that was complete or virtually so. Focal thyroiditis implies focal or spotty collection of lymphocytes with or without a
Histologic Examination
The thyroid specimens were fixed with buffered neutral formalin, and the sections were processed in a routine manner and stained with hematoxylin-eosin. Histologic appearances were estimated independently by two observers (YM and FM) on hematoxyTABLE t.
Case No.
Date of A g e (yrs)/ E x a m i Sex nation
1
24/F
2
34/F
3
47/F
4
28/F
5
34/F
6
36/F
10/80 3/81 11/80 5/81 8/82 1/83 7/83 8/83 10/83 11/83 10/84
15/F
8
33/F
9
62/F
10
45/F
11
15/F
12
36/F
13
33/F
14
17/F
15
48/M
16
43/F
17
20/F
18
46/F
19
54/F
20
47/F
21
40/F
22
30/F
23
48/F
Normal range
-
Free T 4 Ts Free T 3 TSH (ng/dL) (ng/dL) (pg/mL) (IxU/mL)
14.4 6.6 13.4 28.2 7.3 25.4 6.7 12.0 11.0 16.1
2.3 1.7 -
346 116 316 93 252 121 550 106 216 168 192
. -
-
1.4
89
-
9/84 10/84 6/84 11/84 7/84 8/84 10/84 11/84 11/84 7/85 8/85 10/85 12/85 1/86 12/85 2/86 5/85 6/85 1/86 2/86 1/86 3/86 2/86 3/86 2/86 3/86 5/86 6/86 5/86 9/86 7/86 8/86 7/86 9/86
14.3 12.8 17.2 10.0 11.6 5.1 7.3 12.1 -
3.6 0.7 3.7 1.1 3.0 2.2 3.1 1.1 2.2 1.4 2.6 1.3 7.9 1.7 3.4 1.2 3.1 1.2 6.4 1.3 2.3 2.8 2.8 0.7 3.8 2.1 2.7 0.6 4.4 1.2 9.1 4.3 4.2 0.6
224 115 217 121 233 180 198 109 185 156 128 104 295 128 256 103 338 113 157 176 195 91 114 154 70 119 242 85
17.4 4.4 8.2 5.4 7.3 3.1 7.6 4.7 10.6 15.9 8.7 -
-
4.6-11.0
0.7-2.1
95-200
2.3-5.4
11/84
7
T4 (p,g/dL)
Laboratory Data on 23 Patients with Silent Thyroiditis
3 6 <2 5 <2 5 <2 .
R A I U (%)
ESR (mm)
3h
24 h
1h 2 h
2.8 32.1 2.5 . -* . 0.7
1.8 55.3 1.9 . . 0.1
. <2 <2 <2 <2
<2 6 <2 3 <2 <2 <2 <2 <2 <2 <2 <0.2 <0.2 <0.2 9 <2 <2 <0.2 <0.2 <0.2 <2 <2 35 <0.2 <0.2 <2.0 19 <0.2 1.2 <0.2 <0.2 <2 7 <10
. 2.8 . 1.6 . 1.4 . 3.3 . 3.4 . 2.2 . 2.8 2.8 . 1.7 . 1.9 27.9 2.1 1.9 2.1 2.2 3.3 . 3.1 . 1.6 . 4.4 . 2.1 2.5 . 1.6 .
1.1 . 0.2 . 0.3 . 0.8 . 0.9 . 0.3 . 3.0 0.7 . 0.6 . 0.6 68.0 0.7 1.0 0.3 0.7 3.5 . 2.9 . 0.7 . 6.0 . 0.9 1.5 . 0.3 .
7-35
10~t0
MCHA Titer 202 402
8 23 802 . . 5 18 < 1 0 2 . . 16 4 0 <102 . . 11 29 <102 . . 9 28 402 . . 15 33 802 . . 7 11 402 . . 47 94 l02 . . 11 33 802 . . 36 71 202 202 402 . . 802 . . 802 <102 9 24 <102 1602 . . 16 4 0 202 . . <102 . . 802 . . <102 < 102 . . 11 34 402 . . <102
Date of Biopsy
Functional Phase at Time of Biopsy
202 202 1602
3/81
Late recovery
5/81
Late recovery
<102 <102
8/82 1/83 8/83
Thyrotoxic Late recovery Early recovery
<102
11/83
Early recovery
<102
10/84
Thyrotoxic
202
10/84
Early recovery
102 <102
1/84 11/84 8/84
Thyrotoxic Late recovery Thyrotoxic
202
11/84
Early recovery
202 102 802
7/85
Late recovery
10/85
Late recovery
<102
1/86
Early recovery
<102 <102 <102 402
2/86
Early recovery
5/85
Thyrotoxic
2/86
Thyrotoxic
3/86
Thyrotoxic
202
3/86
Early recovery
<102
3/86
Thyrotoxic
802
6/86
Early recovery
<102 < 102 -
5/86 9/86 8/86
Thyrotoxic Late recovery Thyrotoxic
<102
7/86
Thyrotoxic
TGHA Titer
<102
-
-
ABBREVIATIONS: T4, t h y r o x i n e ; T 3, t r i i o d o t h y r o n i n e ; T S H , t h y r o t r o p i n ; R A I U , r a d i o a c t i v e i o d i n e u p t a k e ; ESR, e r y t h r o c y t e s e d i m e n tation rate; TGHA, thyroglobulin-coated tanned erythrocyte hemagglutination; MCHA, microsome-coated tanned erythrocyte hemagglutination. * T h y r o i d was not visualized on the scan with 9 9 m T c O 4 - .
424
SILENTTHYROIDITIS[Mizukami et al.] TABLE 2. Histological Observations on 26 Biopsy Specimens Obtained During Thyrotoxic, Early Recovery, and Late Recovery Phases of Silent Thyroiditis
Histologic Characteristics Pattern of infiltration D e g r e e o f infiltration in focal thyroiditis Hyperplastic follicles
Oxyphilic c h a n g e s
Fibrosis
Follicular d e s t r u c t i o n
Grade
% Replacement
Thyrotoxic Phase
Early Recovery Phase
Late Recovery Phase
5 6 3 0 2 1 3 5 2 6 3 1 1 8 3 0 0 0 2 4 5 7 4 9 2
4 4 1 2 1 1 1 2 4 5 1 1 1 5 2 1 0 0 3 2 3 4 4 4 4
7 0 6 1 0 4 2 1 0 6 1 0 0 5 2 0 0 6 1 0 0 4 3 0 7
Focal Diffuse 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3
L y m p h o i d follicles Giant cells
1-25 26-50 51-100 0 1-25 26-50 51-100 0 1-25 26-50 51-100 0 1-25 26-50 51-100 0 1-25 26-5O 51-100 Present Absent Present Absent
formation of germinal follicles. In focal thyroiditis, the degree of cell infiltration was graded from 1 to 3. Grade 1 indicates less than 25% loss of parenchyma by scattered collections of lymphocytes, grade 2 indicates from 26 to 50% replacement by infiltration, and grade 3 indicates greater than 51% replacement. Hyperplasticfollicle implies cuboidal or slightly columnar epithelium with some irregularity in shape of the follicle or some degree of papillary folding. Oxyphilic change implies swollen, oxyphilic, and granular changes of follicular epitheli. Follicular destruction implies breakdown of follicles with infiltration of degenerated and desquamated epithelium into the follicle and heavy aggregation of lymphocytes around the follicle. The degree of each epithelial and follicular change was also graded from 0 to 3. Grade 0 indicates no replacement of parenchyma, grade 1 indicates 1 to 25% replacement, grade 2 indicates 26 to 50% replacement, and grade 3 indicates greater than 51% replacement. Immunohistochemical Examination
The 26 specimens of thyroid with silent thyroiditis and, for comparison, 20 specimens of thyroid with chronic thyroiditis (16 cases of diffuse thyroiditis and 4 of focal thyroiditis) were examined immunohistochemically for the distribution of T and B lymphocytes infiltrating the thyroid tissues. Control tissues comprised two lymph nodes with nonspecific follicular hyperplasia. For immunohistochemical study, sections of par-
affin-embedded tissue were stained with monoclonal antibodies to T (MT-I) or B lymphocytes (MB-I) (BioScience Products, Emmenbrficke, Switzerland). Both antibodies were used in 1:20 dilution. Both antibodies react in formalin-fixed, paraffin-embedded sections, according to the manufacturer. All sections were stained by the avidin-biotin-peroxidase complex (ABC) method. Briefly, the tissue sections were deparaffinized in xylene and immersed in methanol containing 0.3% hydrogen peroxide for 30 minutes at room temperature. The sections were overlaid with the respective antibody for 30 minutes. After rinses in phosphate-buffered saline, the procedure was continued with conventional ABC reagents (Vector Laboratories, Burlingame, CA). Finally, the slides were immersed in 3,3'-diaminobenzidine solution (0.25 rag/ mL with 0.03% hydrogen peroxide) and counterstained with methyl green. Control sections of lymph nodes were included with each examination and revealed localization of monoclonal antibodies to T-cell and B-cell areas. Negative control specimens were prepared by substitution of phosphate-buffered saline for the primary antiserum. RESULTS Clinical a n d Laboraton/Findings
Table 1 shows the results of the clinical and laboratory assessment of the 23 patients. All patients presented with asymptomatic goiter with normal or somewhat firm consistency. Twenty-two patients were female and 1 was male. The average age at pre425
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sentation was 36.3 -+ 12.7 years. Eight patients (cases 1, 2, 4, 8, 15, 16, 22, and 23) had symptoms of hyperthyroidism of a mild to moderate degree. The other 15 patients had no symptoms of hyperthyroidism and only elevated serum levels of T 3, Y4, o r free T 4. None of the patients complained of pain or tenderness over the thyroid area. The radioactive iodine uptake was measured in 22 patients and was less than 6.0% (24 hour) in all of them. The serum levels of T4, T 3, free T4, o r free T 3 were elevated mildly to moderately. The erythrocyte sedimentation rate was determined in 13 patients and was normal or mildly elevated (< 16 ram/h), except in 2 patients. The serum thyroglobulin titers were elevated in 10 patients, and the serum microsome titers were elevated in 15 patients; however, both titers were relatively low. A transient hypothyroidism was observed in 7 patients
(cases 6, 7, 9, 10, 18, 20, and 21). Two patients (cases 4 and 13) were in the postpartum period. Histologic Findings
Table 2 shows the results of histologic evaluation of 26 biopsy specimens. Lymphocyte infiltration, which varied from minimal to severe, was present in all specimens. The histologic patterns of 11 samples from the toxic phase and those of 8 samples from the early recovery phase were essentially similar and characteristic of this disease. On the other hand, 7 samples from the late recovery phase showed only a pattern of chronic focal thyroiditis with normal follicular architecture. Therefore, the results of the quantitative histologic analysis are described separately.
FIGURE 1 [top). Thyrotoxic phase. A, Case 16. Diffuse infiltration of lymphocytes is observed. Many follicles are disrupted, and giant cells are found within the follicles. There is no evidence of granulomatous lesions of subacute thyroiditis. B, Case 22. Focal infiltration of lymphocytes is observed. Follicles are disrupted, and many macrophages or desquamated follicular cells are contained within the follicles. Oxyphilic epithelial changes are not evident. [Both, x100.] FIGURE 2 [bottom]. Earlyrecovery phase. A, Case 4. Diffuse infiltration of lymphocytes is observed. Marked follicular disruption and lack of oxyphilic epithelium are prominent histologic features, similar to those in the thyrotoxic phase. B. Case 10. The findings are similar to those shown in panel A [Both, x100.]
426
SILENT THYROIDITIS [Mizukami et al.]
. ~
k ",~;
N 7-
FIGURE 3. Late recovery phase. ~ Case 2. Only focal infiltration of lymphocytes is observed. Most of the follicles are intact, but some variation in follicle size is observed. There is no evidence of follicular disruption. B, Case 11. The findings are similar to those shown in panel A, Focal lymphocytic infiltration and slightly larger follicles with a low cuboidal follicular epithelium are observed. [ Both, x40.]
Specimens in Thyrotoxic Phase and in Early Recovery Phase. The number of specimens with focal thyroiditis or diffuse thyroiditis was nearly equal. In the samples of focal thyroiditis, two thirds of the samples showed up to 50% replacement by lymphocyte infiltration. Hyperplastic follicular changes varied greatly with the sample, but the degree was generally greater in the early recovery phase than in the thyrotoxic phase. Oxyphilic changes were absent in 11 of the 19 samples, and 4 showed up to 25% replacement by oxyphilic cell changes; however, the remaining 4 were greater than 26%. Over two thirds of the specimens showed no or minimal fibrosis, and marked fibrosis with severe parenchymal replacement was not observed. Follicular destruction, which characterizes this disease, was observed exclusively in all specimens. The degree of follicular destruction varied greatly in the specimens: 5 showed less than 25% replacement, 6 showed 26 to 50% replacement, and 8 showed greater than 51% replacement. Lymphoid follicles were present in about half the specimens. Giant cells within or around the disrupted follicles were seen in two thirds of the specimens, but typical granulomatous lesions of subacute thyroiditis were not observed in the specimens (fig. I, thyrotoxic phase; fig. 2, early recovery phase). Specimens in Late Recovery Phase. All seven specimens showed focal thyroiditis.The degree of lymphocyte infiltration was minimal or mild, with less than 25% replacement by lymphocyte infiltration. Lymphoid follicles were present in four specimens. The follicular architecture was well preserved and similar to that in the normal thyroid. Follicular destruction, oxyphilic cell changes, and fibrosis were never observed in the specimens (fig. 3, late recovery phase). Follow-up Biopsy Study. Three of the 23 patients had follow-up biopsies done. The first biopsy speci-
men was obtained in the thyrotoxic phase, and the second biopsy specimen was from the late recovery phase, although the period between the first and second biopsies varied. The first biopsy specimens from the toxic phase showed marked follicular destruction and various epithelial changes except epithelial oxyphilia. On the other hand, the second biopsy specimens from the late recovery phase showed only minimal to mild lymphocyte infiltration and normal follicular structure, indicating improvement of histologic features (figs. 4 to 6).
Immunohistochemical Findings Results in control lymph nodes were similar to those obtained previously with monoclonal antibodies of the OKT series. T cells were concentrated in the paracortex, and a small percentage (mean, 20%) were present within germinal centers (fig. 7A). Most germinal centers and cells in the mantle zone stained predominantly with B-cell antiserum (fig. 7B). In both silent thyroiditis and chronic thyroiditis, the 1.ymphocytes formed lymphofollicles in the thyroid nssues and showed a similar distribution of T and B cells to that of control lymph nodes (fig. 7C). T cells were predominantly distributed in the paracortical areas, and B cells were in the germinal centers and mantle zones. In both silent thyroiditis and chronic thyroiditis, a great majority of the lymphocytes infiltrating between thyroid follicles (>99%) showed a T~ cell phenotype (figs. 7D and E). Very few scattered cells showed a B-cell phenotype. No significant differences in distribution of T and B cells were found between silent thyroiditis and chronic thyroiditis. In cases of silent thyroiditis, many T lymphocytes were aggregated around the disrupted thyroid follicles, and some T lymphocytes were also infiltrated within the intrafollicular spaces (fig. 7F). 427
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428
SILENTTHYROIDITIS[Mizukami et aL] FIGURE 4 [top], Case 3. The first biopsy during thyrotoxic phase [left]. Many giant cells are formed within a follicle, and other follicles are not involved. This appearance closely resembles that of early-phase subacute thyroiditis, causing difficulty in differentiating silent thyroiditis from subacute thyroiditis in this case. [• The second biopsy during late recovery phase [right] shows the thyroid is nearly normal. Ix40.] FIGURE 5 [middle], Case 8, The first biopsy during thyrotoxic phase [left] shows marked follicular destruction and diffuse lymphocytic infiltration, characteristic to silent thyroiditis. [x100]. The second biopsy during late recovery phase [right] shows that the degree of follicular destTuction is markedly decreased and the thyroid is almost normal. [• FIGURE 6 [bottom], Case 21, The first biopsy during thyrotoxic phase [left] and the second biopsy during late recovery phase [right]. The findings are similar to those in Case 8 [fig. 5]. An improvement in histologic features is observed, [left,, x 100; right x40.]
DISCUSSION
Thyrotoxicosis with low radioactive iodine uptake is usually associated with subacute thyroiditis or ingestion of exogenous thyroid hormone. Subacute thyroiditis is characterized by transient thyrotoxicosis, painful and tender goiter, fever, elevated erythrocyte sedimentation rate, and low radioactive iodine uptake. Several reports of patients with silent thyroiditis have been published since 1975.1-s This disease is a transient form of thyrotoxicosis characterized by painless, nontender goiter and a low radioactive iodine uptake and differs from subacute thyroiditis in its higher frequency of antithyroid antibodies, absence of the very high erythrocyte sedimentation rate, and absence of pain and tenderness. Histologically, silent thyroiditis shows a pattern with consistent chronic thyroiditis; giant cell granuloma, which is characteristic of subacute thyroiditis, is not observed. Nikolai et al. 6 described the histologic findings of biopsy specimens from 12 patients with silent thyroiditis as m o d e r a t e - f o c a l or diffuselymphocytic infiltration, follicular disruption, occasional oxyphilic changes, minimal or no fibrosis, and no germinal centers. Gorman et al. 5 reported 4 cases of silent thyroiditis, showing lymphocytic infiltration and extensive follicular destruction without oxyphilia. No case of subacute thyroiditis was seen in either study. In the present study, we reviewed 26 specimens from 23 patients. The histologic features were essentially consistent with chronic lymphocytic thyroiditis. The most cogent differences in histologic features of silent thyroiditis were a pronounced follicular destruction and a lack of oxyphilic changes, as pointed out by Gorman et al. 5 Such an extensive follicular destruction is not seen in ordinary chronic thyroiditis, and this finding seems to be useful in differentiating silent thyroiditis from other forms of thyroiditis. This extensive follicular destruction also indicates that the thyrotoxic state in silent thyroiditis results from release of stored hormone into the circulation following follicular destruction, just as in subacute thyroiditis. It has been shown that follicular d e s t r u c t i o n is also seen in c h r o n i c " j u v e n i l e " thyroiditis 9 and palpation thyroiditis. 1~ In both diseases, however, follicular destruction is more sporadic and sparse than in silent thyroiditis, and thyrotoxicosis is usually not associated. Chronic thyroiditis presenting with thyrotoxicosis has been known and is sometimes encountered in the clinic. This disorder is characterized by nontender painless thyroid, elevated levels of T 4 and T 3, 429
and elevated uptake of radioactive iodine. This disorder is the so-called hashitoxicosis. 11 Hashitoxicosis usually requires treatment with antithyroid drugs to terminate hyperthyroidism. On the other hand, silent thyroiditis is self-limiting and does not require therapy for hyperthyroidism. Histologically, hashitoxicosis shows combined features of Graves' disease and chronic thyroiditis, with no or minimal follicular destruction. Therefore, thyroid biopsy seems to be useful in distinguishing silent thyroiditis from hashitoxicosis. Inada et a1.12 reported that histologic abnormalities, such as lymphocytic infiltration and follicular epithelial changes, were alleviated spontaneously within several months in two patients with silent thyroiditis. In the present study, follow-up biopsies were p e r f o r m e d in three patients. Each second biopsy specimen showed only mild lymphocytic infiltration and no evidence of follicular destruction. This finding indicates not only recovery of clinical and laboratory findings but also recovery of histologic features in the course of silent thyroiditis. Postpartum thyroiditis, which is characterized by a reversible thyrotoxic or hypothyroid phase during the y e a r a f t e r c h i l d b i r t h , has also b e e n recognized.I3'~4 The histologic features of the thyroid in this condition have been obscure. Inada et al. 15 reported one case of postpartum thyroiditis in which the histologic appearance of the thyroid was similar to that in silent thyroiditis. In our study, two patients were in a postpartum period, and the histologic features of their thyroid glands were similar to those in other patients with silent thyroiditis, i.e., diffuse or focal lymphocytic infiltration and marked follicular destruction. This result suggests that both silent thyroiditis and postpartum thyroiditis can be fitted into the same category, and a similar factor may induce both thyroiditides. The pathogenesis of silent thyroiditis is not clear9 Morrison and Caplan 1 reported one case of typical subacute thyroiditis and one of silent thyroiditis in a wife and husband and suggested that silent thyroiditis is in the range of subacute thyroiditis (atypical subacute thyroiditis). Nikolai et al. ~ investigated the viral antibody response for a range of viruses in this disease, but no definite evidence for a viral etiology was 9 obtained. On the other hand, Amino et al. l o suggested that autoimmunity plays an important role in the pathogenesis of silent thyroiditis as well as in H a s h i m o t o ' s d i s e a s e , a n d at p r e s e n t , m a n y investigators 17-2~ believe that this disease is due to enhancement of i m m u n e activity9 Jansson et al. 19
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SILENT THYROIDITIS [Mizukami et al.] FIGURE 7. A, Control lymph node stained with MT-I for T cells. MT I + lymphocytes are concentrated in the paracortex area. Some are also present in the germinal center and follicular mantle. B, Control lymph node stained with MB-I for B cells. MB-I + lymphocytes are predominantly distributed in the mantle and germinal centers. C, Thyroid with chronic thyroiditis stained with MB-I. Only lymphocytes in the follicular mantle are positive. Lymphocytes scattered between thyroid follicles are negative. D, Thyroid with chronic thyroiditis stained with MT-I.A great majority of infiltrating lymphocytes are positive for MT-I, E, Thyroid with silent thyroiditis stained with MT-I. All lymphocytes infiltrating between thyroid follicles are positive for MT-I. F. Thyroid with silent thyroiditis stained with MT-I. A dense accumulation of MT-I + lymphocytes is observed around the disrupted follicle. Some MT-I § lymphocytes are also observed within the follicular lumen. JAil, methyl green counterstains, A, D, E, and F, x200; B and C, xfl00.]
Acknowledgments. T h e a u t h o r s t h a n k Dr. M. Kawato for critical c o m m e n t s a n d Sanae Itoh for h e r assistance in the p r e p a r a t i o n of the m a n u s c r i p t .
showed a relative accumulation of B cells and a relative decrease of suppressor-cytotoxic T cells in the thyroid tissues of this disease. Elliot et al. 2~ also reported a predominant infiltration of T cells, especially helper-inducer T cells, in the thyroid tissues in this disease. These studies on local lymphocyte subsets suggest the importance of local autoantibody production in the pathogenesis of this disease. In the present immunohistochemical study, a great majority of the infiltrating lymphocytes were T cells, and no differences in distribution of T and B cells were observed as compared to that in chronic thyroiditis. No evidence of accumulation of B cells was found, in contrast to the report ofJansson et al. 19 The monoclonal antibody against T cells used in this study is unable to distinguish suppressor-cytotoxic T cells from helper-inducer T cells. Therefore, we were unable to determine a relative distribution of each T-cell subset. We presume that thyrotoxicosis in this disease results from destruction of thyroid follicles. Therefore, it is of interest whether follicular destruction is caused by a cytotoxic effect of infiltrating T cells. We would like to assume that the inflammatory process of this disease is extremely rapid and thyroid follicles are easily destroyed by the cytotoxic effects of the infiltrating T lymphocytes. We are attempting to quantify intrathyroidal T-cell subsets using the monoclonal antibody O K T series. The absence of oxyphilic cell changes or stromal fibrosis, which is also a histologic feature characteristic of this disease, is probably due to the rapid progression of inflammation in this disease. Woolner et al. 8 classified chronic thyroiditis into focal thyroiditis and diffuse thyroiditis and further divided diffuse thyroiditis into four subtypes on the basis of epithelial changes, stromal fibrosis, and cell infiltration. Woolner and colleagues' classification of chronic thyroiditis has been the one used most frequently by pathologists, because for each subtype, the histologic appearances and functional effects are consistent. However, a description concerning chronic thyroiditis associated with such an extensive follicular destruction could not be found in this classification. We found that silent thyroiditis is essentially in the entity of chronic thyroiditis and that the extensive follicular disruption is the differential diagnostic point in assessment of silent thyroiditis. The thyrotoxicosis in this disease is transient and self-limited, and usually treatment is unnecessary. Therefore, this disease should be differentiated from other forms of thyroiditis, such as subacute thyroiditis, Graves' disease, or hashitoxicosis. We would like to refer to this disease as "chronic thyroiditis with marked follicular destruction" from the standpoint of pathologists.
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