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Chronic thyroiditis: Thyroid function and histologic correlations in 601 cases
Chronic Thyroiditis: Thyroid Function and Histologic Correlations in 601 Cases
YUJI MIZUKAMI, MD, TAKATOSHI MICHIGISHI, MD, MASANORI KAWATO, MD, TAMOTSU SATO, MD, AKITAKA NONOMURA, MD, TAKUMA HASHIMOTO, AND FUJITSUGU MATSUBARA, MD Six hundred one patients with histologically proven “chronic thy roiditis” were assessed for the correlation of thyroid function to histologic findings. The histology of chronic thyroiditis was classified $to four groups (oxyphilic, mixed, focal, and hyperplastic), and the thyroid function of patients was divided into hyperthyroid, euthyroid, latent hypothyroid, and overt hypothyroid, based on the laboratory data of serum triiodothyronine (T3), thyroxine (T4), and thyrotropin (TSH) levels, as well as thyrotropin-releasing hormone (TRH) tests. In the oxyphilic group (137 cases), 116 (85%) of the patients were classified as hypothyroid: 52 (38%) as latent hypothyroid and 64 (47%) as overt hypothyroid. In the mixed group (161 cases), the thyroid function of the patientsvaried. Thirty-seven(23%) of the patientswere classifiedas hyperthyroid,61(39%) as euthyroid, 54 (33%) as latent hypothyroid, and nine (5%) as overt hypothyroid. In this group thyroid function was intimately related to the ratio of replacement by hyperplastic-changed follicles and oxyphilicchanged follicles. In the focal group (149 cases), 123 (83%) of the patients were classified as euthyroid, while 22 (14%) were classified as latent hypothyroid. The frequency of latent hypothyroid patients increased in parallel with the severity of cell infiltration. In the byperplastic group (154 cases), 130 (85%) of the patients were classified as hyperthyroid. In this series 19 patients under 10 years of age were included, and no difference in the distributionof histologic varietieswas observed betweenjuvenile and adult patients. Thyroid needle biopsy is a useful and safe tool, not only for the histologic diagnosis of chronic thyroiditis,but also for the evaluationof thyroid function and the identification of causes for hyperthyroidism or hypothyroidism. Hm PATHOL 23:980-988. Copyright 0 1992 by W.B. Saunders Company
Histologic features of the thyroid gland in patients with “chronic thyroiditis” are considerably varied and reveal a broad spectrum. Several histologic classifications of chronic thyroiditis have been proposed, such as the Doniach and Roitt classification,’ the Hazard classification,” the classification of Woolner et a1,3 and the LiVolsi classification.” However, few large-scale studies have focused on the correlation between thyroid func-
MD,
tion and histologic findings of chronic thyroiditis. Such attempts have been made by pathologists and endocrinologists. It used to be thought that extrapolation of functions from the histologic appearance of thyroid gland is too inconsistent for clinical purposes.
From 1975 to 1980 at Kanazawa University Hospital (Kanazawa, Japan), an extensive clinical and pathologic exploration project on chronic thyroiditis was carried out. In this project frequency of patients, physical findings of patients, detailed thyroid function state, circulating thyroid antibodies, and histologic changes of thyroid gland corresponding with these clinical data were examined by both endocrinologists and pathologists. 5-7 At that time most of these findings, especially the histologic findings of the thyroid gland in this disease, were not sufficiently clarified. We are now reviewing the clinical and histologic data obtained during the project and are convinced that these data on chronic thyroiditis, especially the data on thyroid function and histologic findings of thyroid gland, will provide a meaningful basis for a comparison between clinical status and histologic findings in chronic thyroiditis. Most of the patients (430 patients) were included in an earlier report* that was written in Japanese. The current report deals with the original study’s 430 patients and 171 additional patients.
MATERIALS
AND METHODS
Six hundred one patients from Kanazawa University Hospital between 1975 and 1980 were included in this study. Patients were chosen because they had thyroid biopsies with histologic evidence of mononuclear cell infiltration. The patients who underwent large needle biopsy of the thyroid gland were limited to those presenting with findings of both a diffuse goiter of various degrees and positive circulating thyroid antibodies (ie, those clinically diagnosed as having chronic thyroiditis). Patients with typical Graves’ hyperthyroidism or with simple goiter were excluded from the needle biopsy examination. In most cases sera were obtained from untreated patients in the month prior to biopsy and stored at -20°C until determination, but in a few cases referred to us from other hospitals propylthiouracl or methimazole treatment for hyperthyroidism had been performed. Also, in a few patients with florid toxic symptoms biopsies were performed after 1 month of propylthiouracil or methimazole administration. Patients with transient hyperthyroidism or hypothyroidism, sug-
From the Pathology Section, Departments of Nuclear Medicine. Internal Medicine, Laboratory Medicine, and Pediatrics, Kanazawa University Hospital, Kanazawa, Japan. Accepted for publication March 4,1991. Kq words: thyroid needle biopsy, chronic thyroiditis, histologic classification, thyroid function, thyrotropin-releasing hormone test. Address correspondence and reprint requests to Yuji Mizukami, MD, Pathology Section, Kanazawa University Hospital, 13-1, Takaramachi, Kanazawa, 9‘20. Japan. Copyright 0 1992 by W.B. Saunders Company 0046-8177/92/2X)9-0003$5.00/O
980
CHRONIC THYROIDITIS:
TABLE
FUNCTION
AND HISTOLOGY
1. Evaluation of Thyroid Function Serum Level of T3 and T4
Thyroid Function Hyperthyroid
High
Euthyroid
Normal range T3: 88-177 ng/dL T4: 6.3-13.5 pg/ dL Normal - low normal Low
Latent hypothyroid Overt hypothyroid
Pathologic Examination
TRH Test No - low response ATSH: <5 pU/mL Normal response ATSH: 5-29 pU/mL Exaggerated response ATSH: 30-85 pU/mL Exaggerated response ATSH: >85 pU/mL.
Note: ATSH, the value of increased thyrotropin to thyrotropinreleasing hormone.
gesting postpartum hypothyroidism or silent (painless) thyroiditis, were excluded from this study. Of the 601 patients, 545 underwent a large needle biopsy using a Silverman’s needle. Needle biopsy specimens were obtained from both thyroid lobes in most cases; however, in a few cases sufficient specimens for diagnosis were obtained from only one thyroid lobe. Our colleagues (endocrinologists) were well experienced in the procedure of large needle biopsy, and all biopsies were safely carried out with the patient’s approval and with no complications. The remaining 56 patients underwent surgical biopsies. Serum thyroxine (T4) was measured by competitive protein-binding analysis with a Tetrasorb-125 kit (Abbott Laboratories, Abbott Park, IL). The normal range was 6.3 to 13.5 pg/dL. Serum triiodothyronine (T3) was determined by radioimmunoassay. The normal range was 88 to 177 ng/dL. Serum thyrotropin (TSH) was measured by radioimmunoassay using the double antibody method. The thyrotropin-releasing hormone (TRH) stimulation test was carried out by intravenous injection of 500 PcLg TRH (Tanabe Pharmaceutical Co, Osaka, Japan) and serum for the TSH assay was drawn before and at 20, 40, 60, and 90 minutes after the administration of TRH. The normal range of basal TSH was less than 5 pU/mL, and the increased TSH to TRH (ATSH) ratio was 5 to 29 pU/mL. On the basis of the T3, T4, basal TSH level, and increased TSH to TRH ratio, at least four groups could be distinguished as follows: hyperthyroid, euthyroid, latent hypothyroid, and overt hypothyroid. The outlined criteria are presented in Table 1.
TABLE 2. Histologic Group
(Mizukami et al)
The thyroid specimens were divided into four histologic groups in terms of the replacement of both lymphocytic infiltration and altered follicular epithelium. Our classification was primarily based on Woolner et al’s classification of chronic thyroiditiss (Table 2). Chronic thyroiditis, oxyphilic. The thyroid gland shows a diffuse interfollicular infiltration of mononuclear cells and diffuse epithelial oxyphilic changes with mild to severe stromal fibrosis. Oxyphilic-changed epithelium has a swollen, oxyphilic, and granular cytoplasm. This group includes three subgroups of diffuse thyroiditis in Woolner et al’s classification’: diffuse thyroiditis with oxyphilic epithelium, pronounced epithelial destruction, and lymphoid type (Fig 1). Chronic thyroiditis, mixed. The thyroid specimen shows more or less diffuse infiltration of mononuclear cells and a mixture of altered follicular cells, composed of oxyphilic, hyperplastic, normal, and unclassified epithelial change. This group corresponds to Woolner et al’s subgroup of diffuse thyroiditis with varied epithelial changess (Fig 2). Chronic thyroiditis, focal. The thyroid specimen shows a focal or spotty collection of mononuclear cells and minimal changes in follicular epithelium or stromal fibrosis, corresponding to Woolner et al’s major group of focal thyroiditis.’ In this group the extent of cell infiltration was graded from mild to marked. Mild indicates a less than 10% loss of parenchyma by scattered collections of mononuclear cells, moderate indicates a 10% to 50% replacement by cell infiltration, and marked indicates a greater than 50% replacement (Fig 3). Chronic thyroiditis, hyperplastic. The specimen shows difluse hyperplastic changes of follicles. Follicular cells are cuboidal or slightly columnar and follicles show some irregularity in shape or some degree of papillary folding. Mononuclear cell infiltration is mild. This group includes Woolner et al’s subgroup of thyroiditis with hyperplastic epitheliums (Fig 4). In addition to the histologic classification of the oxyphilic, mixed, focal, and hyperplastic groups in 601 cases, the percentage of loss of parenchyma by fibrosis was evaluated in each case of the oxyphilic group, and the ratio of replacement by each follicular epithelial change (oxyphilic, hyperplastic, normal, and unclassified) was evaluated in each case of the mixed group. Statistical analysis was performed using Student’s t-test. Differences were judged to be significant at a confidence level greater than 95% (P < .05).
Histologic Classification
of Chronic Thyroiditis
Histologic Findings
Chronic thyroiditis, oxyphilic
Diffuse cell infiltration: moderate to severe Oxyphilic epithelial changes: almost all Fibrosis: mild to severe
Chronic thyroiditis, mixed
Diffuse cell infiltration: moderate Follicular epithelial changes: various (oxyphilic, hyperplastic, and normal) Fibrosis: minimal to mild
Chronic tbyroiditis, focal Mild Moderate Marked Chronic thyroiditis, hyperplastic
Focal cell infiltration Extent of cell infiltration50% Focal cell infiltration: mild to moderate Diffuse hyperplastic epithelial changes: mild to severe
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Corresponding Diffuse thyroiditis, Diffuse thyroiditis, Diffuse thyroiditis, destruction Diffuse thyroiditis,
Woolner’s
Classification
oxyphilic epithelium lymphoid type pronounced epithelial varied epithelial changes
Focal thyroiditis
Thyroiditis with “hyperplastic”
epithelium
HUMAN PATHOLOGY
Volume 23, No. 9 (September
1992)
FIGURE 1. Oxyphilic group. (Left) Diffuse heavy interfollicular infiltration of mononuclear cells and diffuse epithelial oxyphilia are observed. (Hematoxylin-eosin stain; magnification X78.) (Right) Extensive stromal fibrosis with follicular atrophy is predominant. (Hematoxylin-eosin stain; magnification X78.)
RESULTS Clinical Findings The age and sex distribution of the 601 patients is shown in Fig 5. Five hundred forty-seven patients were female and 54 were male (female to male ratio, 10: 1). Five hundred thirty-four (89%) of the 60 1 patients were between 20 and 60 years of age; 19 patients were under 10 years of age and 48 were over 61 years of age. The median age of all patients was 37.9 years. In relation to the histologic groups the median age of the patients was highest in the oxyphilic group (44.3 years) and, in descending order, mixed group (37.7 years), focal group (37.4 years), and hyperplastic group (32.9 years). The percentage of the cases of the oxyphilic group increased in accordance with aging. On the other hand, the percentage of cases of the hyperplastic group decreased after 40 years of age (Table 3). Correlation of Thyroid Function of Patients to Their Histologic Groups The distribution of all patients by histologic group, thyroid function, and age is shown in Table 3 and Fig
6. In the oxyphilic group, 116 (85%) of 137 patients were hypothyroid. Fifty-two (38%) patients were latent hypothyroid and 64 (47%) were overt hypothyroid. Only four (3%) patients were hyperthyroid and 17 (12%) patients were euthyroid. In this group the relationship between the thyroid function or age of the patients and the extent of stromal fibrosis in their thyroid specimens was examined in 89 patients from whom sufficient thyroid specimens were obtained for this evaluation (Fig 7). There was a correlation found between the age of the patients and the extent of fibrosis in the thyroid specimens from 49 patients with overt hypothyroidism (r = .518). This finding suggested that in younger patients hypothyroidism might be caused by the involvement of thyroid hormone synthesis in the oxyphilic changed epithelium while, on the other hand, in older patients increased stromal fibrosis generally accompanied hypothyroidism. In the mixed group, 37 (23%) of the 161 patients were hyperthyroid, 61 (39%) euthyroid, and 54 (33%) latent hypothyroid. Only nine patients were overt hypothyroid. For quantitative histologic evaluation, to
FIGURE 2. Mixed group. (Left) Diffuse interfollicular infiltration and variously changed epithelium composed of oxyphilic, hyperplastic, and normal epithelium are observed. (Hematoxylin-eosin stain; magnification X100.) (Right) Higher magnification discloses oxyphilic (0). hyperplastic (h), and normal (n) epithelium. (Hematoxylin-eosin stain; magnification x400.)
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CHRONIC THYROIDITIS:
FUNCTION
AND HISTOLOGY
(Mizukami et al)
FIGURE 3. (Top left) Focal, mild group. Focal lymphocytic infiltration is observed in a normal-appearing background. The extent of replacement by cell infiltration is less than 10%. (Hematoxylin-eosin stain; magnification x3 1.) (Top right) Focal, moderate group. The extent of cell infiltration is from 10% to 50%. (Hematoxylin-eosin stain; magnification X31.) (Bottom) Focal, marked group. The extent of cell infiltration is more than 50%. (Hematoxylin-eosin stain; magnification x31 .)
clarify the relationship between the histologic appearance and the thyroid function of the patients in this group, the altered follicular epithelium was classified into the following four types: hyperplastic, oxyphilic, normal, and unclassified. The mean amounts of replaced area by each type of altered follicular epithelium were estimated in each specimen. The results were as follows. In thyroid specimens from patients of the hyperthyroid
group the mean value of replacement by hyperplastic epithelium was approximately 37%, whereas that by oxyphilic epithelium was 29%. On the other hand, in the latent hypothyroid group the mean value of replacement by hyperplastic epithelium markedly decreased to 3%, and that by oxyphilic epithelium increased to 62% (Fig 8). This finding indicated that the thyroid function of patients in the mixed group was closely related to the composition ratio of hyperplastic-changed epithelium and oxyphilic-changed epithelium in their thyroid specimens. In the focal group, 123 (83%) of the 149 patients were euthyroid, three (2%) were hyperthyroid, and 22 (14%) were latent hypothyroid. Only one patient was overt hypothyroid. In relation to the extent of cell infiltration (mild, moderate, and marked), the frequency of latent hypothyroid patients increased in accordance with the enlargement of the area of cell infiltration from mild to marked: 7% of patients in subgroup mild, 15% in moderate, and 26% in marked. The difference was significant: P < .05 (Table 4 and Fig 9). The median ages of patients in the focal group increased as follows: mild (36.9 years), moderate (37.3 years), and marked (37.5 years). In the hyperplastic group, 130 (85%) of the 154 patients were hyperthyroid, eight were euthyroid, five were latent hypothyroid, and 11 were overt hypothyroid. Most of these 24 euthyroid or hypothyroid patients had
FIGURE 4. Hyperplastic group. Diffusely hyperplastic epithelial changes and mildly focal lymphocytic infiltration are observed. (Hematoxylin-eosin stain; magnification x100.)
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HUMAN PATHOLOGY
Volume 23, No. 9 (September
1992)
110 100 [
0
FIGURE 5. Sex and age distribution of 601 patients with chronic thyroiditis. hundred forty-seven pati%t: are female (open bars) and 54 are male (shaded bars). The number above each column indicates the number of oatients.
3s
L 3
:::.
0 - 10
11
-a,
31 - 40
21 - 30
51 - 60
41 - 50
We
been treated with propylthiouracil the time of their serum sampling. Chronic Thyroiditis
or methimazole
at
11 - a0
J.0.
DISCUSSION Since 1950, hormonal and immunologic studies of chronic thyroiditis have progressed extensively, and the diagnosis and evaluation of the functional state in patients with chronic thyroiditis have been relatively easily carried out. At the same time, histologic examination of the thyroid gland using the large needle biopsy method also has been routinely performed for histologic diagnosis of chronic thyroiditis. In our hospital, not only fine needle aspiration biopsy of the thyroid gland, but also large needle biopsy, which yields a histologic specimen, have been used successfully and safely by physicians since 1972 for the diagnosis of thyroid disease.
in Childhood
Thyroid specimens from the 19 patients under 10 years of age who were considered to be in the earlier stage of the disease were also divided histologically into oxyphilic, mixed, focal, and hyperplastic groups. In the oxyphilic group four of five patients were latent hypothyroid and in the mixed group all four patients were hyperthyroid. In the focal group all three patients were euthyroid and in the hyperplastic group all seven patients were hyperthyroid (Table 3 and Fig 10).
TABLE 3.
61 - 10
I
2
Functional Distribution of 601 Patients With Chronic Thyroiditis
by Histologic Group and Patient Age
Age (yr) Total Histologic
Group
1 l-20
21-30
31-40
41-50
51-60
61-70
5 1
5 1
21 1
18 5
28 4
39 3
Hyperthyroid Latent hypothyroid Overt hypothyroid
0 4 0
0
0
I
8
3
12
3 4 6
0 8 16
Mixed (total) Euthyl-oid Hyperthyroid Latent hypothyroid Overt hypothyroid
4 0 4 0 0
27 8 10 9 0
19 5 6 5 3
34 17 5 10 2
Focal (total) Euthyroid Hyperthyroid Latent hypothyroid Overt hypothyroid
3 3 0 0 0
26 25 1 0 0
23 17 1 5 0
Hyperplastic (total) Euthyroid Hyperthyroid Latent hypothyroid Overt hypothyroid
7 0 7 0 0
24 1 23 0 0
46 2 37 3 4
Oxyphilic (total) Euthyroid
Note: Data are expressed
O-10
as number
of patients
71-80
(%)
17 2
4 0
137 17 (12)
0 17 19
0 10 5
1 0 3
4 (3) 52 (38) 64 (47)
38 19 4 13 2
28 9 5 13 1
10 3 3 3 1
1 0 0 1 0
161 61 37 54 9
(39) (23) (33) (5)
25 20 0 5 0
38 31 1 6 0
22 16 0 5 1
10 9 0 1 0
2 2 0 0 0
149 123 3 22 1
(83) (2) (14) (1)
31 3 26 1 1
14 1 12 0
28 1 22 1 4
2 0 1 0 1
2 0 2 0 0
154 8 130 5 11
(5) (85) (3) (7)
in each category.
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I
CHRONIC THYROIDITIS:
FUNCTION
AND HISTOLOGY
(Mizukami et al)
FIGURE 6. Frequency of patients with hyperthyroid (solid bars), euthyroid (dotted bars), latent hypothyroid (striped bars), and overt hypothyroid (open bars) in each histologic group (oxyphilic, mixed, focal, and hyperplastic). Parentheses indicate percentage of patients exhibiting each thyroid function. riyperplastic group (154 w.ses
Large needle biopsy is a safe and accurate method to make a tissue diagnosis of chronic thyroiditis as well as nodular lesions. Based on a large number of cases (625 needle biopsies), Hawk et al9 reported that struma lymphomatosa lesions are suitable for large needle biopsy. In her recent textbook on the surgical pathology of the thyroid gland, LiVolsi” explains that morphologic diagnosis of thyroiditis can be more readily established with this technique. At present, when doing a histologic examination of the thyroid gland, pathologists are required not only to make a histologic diagnosis of chronic thyroiditis, but also to evaluate the thyroid function of the patient or to confer with the clinician concerning the treatment of the patient. However, few histologic studies have been
reported that place emphasis on detailed thyroid function in patients with chronic thyroiditis. Therefore, in this study we attempted to elucidate the correlations between thyroid function and thyroid histology in patients with chronic thyroiditis from the standpoint of a re-evaluation of Woolner et al’s classification of chronic thyroiditis3 We believe that the data described here provide a foundation for interpretation of morphologic changes in chronic thyroiditis in relation to thyroid function. Diffuse and more extensive mononuclear cell infiltration and uniform oxyphilic epithelial changes were characteristic histologic features of thyroid specimens in the oxyphilic group. Our previous enzyme histochemical study” showed that these oxyphilic-changed epithelia are lacking in the activity of peroxidase, an essential enzyme for the biosynthesis of thyroid hormone. Therefore, it is understandable that the majority of patients in the oxyphilic group were hypothyroid. A decrease of thyroid parenchyma due to stromal fibrosis is also an important contributing factor, and an increase in the extent of stromal fibrosis was associated with aging of the patients. Recently, hypothyroidism has been classified into two groups in view of its clinical course: reversible and irreversible hypothyroidism. The distinction of these types is sometimes difficult from analysis of clinical and laboratory data. The thyroid gland in patients with transient, reversible hypothyroidism usually reveals the histologic features of the mixed type of chronic thyroiditis in our classification, or chronic thyroiditis with extensive follicular destruction as described in our previous study of “silent thyroiditis.“” On the other hand, a thyroid gland revealing irreversible hypothyroidism shows a pronounced epithelial exyphilla and stromal fibrosis of various degrees. We consider thyroid needle biopsy to be a useful and key diagnostic tool in the differentiation of both types of hypothyroidism. In the mixed group, thyroid function of patients was dependent on the composition ratio of replacement by
. .
FIGURE 7. Relationship between thyroid function, age of patients, and extent of fibrosis in thyroid specimens in the histologic oxyphilic group. In 49 patients with overt hypothyroidism, a correlation between patients’ ages and extent of fibrosis is observed (y = 0.5x - 3.6; r = 518). Open circles, euthyroid patients; open triangles, latent hypothyroid patients; solid circles, overt hypothyroid patients.
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HUMAN PATHOLOGY
Volume 23, No. 9 (September
20
40
60
80
I
I
I
I
1992)
100
% I
FIGURE 8. Mean percentage of replacement by oxyphilic (small-dotted bars), hyperplastic (striped bars), normal (large-dotted bars), and unclassified (open bars) follicular changes in thyroid specimens from patients of the histologic mixed group. Numbers indicate mean percentoges of replacement.
Ayperthyroid patients
(n=37)
Euthyroid patients
(n=bl)
-.__
La tent
-.
‘\
*. . S. 27 ‘\ 62 ‘_‘.‘_‘.‘.‘.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.’.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~...~.....~.~,~,~.~.~.~,‘,~.‘.‘.‘.‘.~. hypOthyro
i
d
ll l l l l
::i:i:i:i:_:i:i:i:::i:::::i:i:i:i:i:i:i:-:::-:-:::::::~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:i:::_:::i:i:::~:::~:i:i:i:::~~
f
........_.................................................... . . . . . . . . . . . . . . . . . .._................_.................. ~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~,~.~.~..,..~.~.~.~.~.~.~,~.~.~.~.~.~.~.~ _.... ....~.~.~.~.~_~.~.~.~.~.~.~.~.~. •.“.v.v.~ ‘.~.‘.‘.‘.~.‘.‘.‘.‘.‘.~.‘.‘.‘.‘.~.’.’.’.’.’.~.~.~.‘.‘.~.‘.~.’.~.‘.~.‘.~.‘.~.‘.‘.~.~.~.~,~,~.’,’.‘.~.~.~.~.‘.‘.‘.‘.‘. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .._........... eeeae
patients (n= 54)
~..........................~..............._................
hyperplastic- and oxyphilic-changed epithelium. Patients with thyroid gland revealing more than 40% replacement by hyperplastic-changed epithelium were usually in a hyperthyroid state. On the other hand, thyroid specimens from hypothyroid patients showed an increased rate of replacement (mean, 62%) by oxyphilic-changed epithelium and a markedly decreased rate of replacement (mean, 3%) by hyperplastic-changed epithelium. “Hashitoxicosis,” a term proposed by Means et al,‘” has been regarded as a clinical entity of concurrent chronic thyroiditis and Graves’ disease. Histologic criteria for hashitoxicosis are controversial.‘4.‘5 Fatourechi et alI5 defined this disorder as hyperthyroidism with the pathologic features of Hashimoto’s disease. Based on our present study, we would like to propose three histologic criteria for hashitoxicosis: the patient is in a hyperthyroid state, the thyroid specimen from the patient is classified as belonging to the mixed group, and the thyroid specimen reveals more than 50% replacement by hyperplastic-changed epithelium. For the other histologic characteristics of the mixed group, the changes in the ratio of replacement by hy-
TABLE 4.
Functional
perplastic- or oxyphilic-changed epithelium in thyroid specimens are not infrequently observed in association with functional alteration of patients during a relatively short period (several months). We have encountered such a condition by follow-up thyroid biopsies.“j Such a histologic and functional alteration may be observed more frequently after a few weeks of treatment, especially in patients receiving treatment with antithyroid drugs against hyperthyroidism, and, subsequently, patients may develop hypothyroidism. Careful attention should be paid to the treatment of the hyperthyroid patients whose thyroid is histologically classified as belonging to the mixed group. In the focal group, most patients have been thought to be euthyroid. However, Takeda et al6 reported that 47% of the patients with focal thyroiditis showed an exaggerated response to TRH. In our study, 14% of the patients in the focal group were latent hypothyroid. Furthermore, in relation to the subgroups, 7% of the patients in subgroup mild, 15% in moderate, and 26% in marked were latent hypothyroid. Therefore, there was a tendency toward an increase in the frequency of
Distribution of 149 Patients With Focal Thyroiditis of Cell Infiltration (Mild to Marked) and Patient
(Focal Aae
Group)
by Extent
Age tyr) O-10
1 l-20
Mild (total) Euthyroid Hyperthyroid Latent hypothyroid Overt hypothyroid
1 1 0 0 0
Moderate (total) Euthyroid Hyperthyroid Latent hypothyroid Overt hypothyroid
2 2 0 0 0
Marked (total) Euthyroid Hyperthyroid Latent hypothyroid Overt hypothyroid Note: Data are expressed
as number
21-30
31-40
41-50
51-60
10 10 0 0 0
10 8 1 1 0
9 8 0 1 0
10 10 0 0 0
9 8 1 0 0
10 7 0 3 0
12 11 0 1 0
7 7
3 2
0 0
01 0
of patients
61-70
71-80
Total (%)
7 5 0 2 0
5 5 0 0 0
1 1 0 0 0
53 48 (91)
19 14 1 4 0
10 7 0 2 1
2 2 0 0 0
1 1 0 0 0
65 52 (80) 2 (3) 10 (15)
4 1
9 7
5 4
3 2
31 23 (74)
03 0
20 0
01 0
01 0
: (26) 0
in each category.
986
1 (2) 4 (71 0
1 (2)
CHRONIC
THYROIDITIS:
FUNCTION
AND HISTOLOGY
5
patients with latent hypothyroidism in accordance with an increase in the extent of cell infiltration. In the hyperplastic group, the great majority of patients were hyperthyroid. Eight patients were euthyroid and 16 patients were hypothyroid, but most of these 24 patients were under propylthiouracil or methimazole treatment. We have previously reported histologic changes (an increase in the extent of cell infiltration and follicular epithelial degeneration) in Graves’ thyroids after long-term treatment with antithyroid drugs.” In the present study the histologic picture of the thyroid gland from these euthyroid or hypothyroid patients after treatment showed a relatively heavy focal cell infiltration, a disappearance of hyperplastic changed epithelium, and an increase of degenerated epithelium showing a swollen, vacuolated, or eosinophilic granular cytoplasm. Consequently, it was difficult to histologically distinguish the hyperplastic group from the mixed group. In addition, a pronounced hyperplastic change of the thyroid gland might be observed in patients with iodine-induced hypothyroidism associated with chronic thyroiditis. Our earlier studies”*‘” dealing with bromine-induced and iodine-induced hypothyroidism disclosed that the thyroid gland in both diseases shows characteristic histologic changes, not only extensive hyperplastic changes but also clear and vesicular cytoplasmic change of follicular cells and depletion of colloid material in the follicular lumen. In iodine-induced hypothyroidism, only restriction of excess intake of dietary iodine readily restored euthyroidism. Attention should be paid to hypothyroid patients whose thyroid is histologically classified as belonging to the hyperplastic group. In recent years chronic thyroiditis has been recognized as a common cause of goiter in children.1g-23 In our study 19 childhood cases were observed. The clinical and pathologic analyses of these cases may be interesting from the viewpoint of the clarification of the natural course of chronic thyroiditis. It has been generally considered that focal thyroiditis is an earlier stage of chronic thyroiditis and that diffuse thyroiditis is a later stage of the disease. However, our study indicated that both focal and diffuse types of chronic thyroiditis might develop independently earlier in life. The juvenile form of chronic thyroiditis has been considered by some investigators to differ from the other types pathologbecause follicular oxyphilia is usually mild or absent, but hyperplastic epithelial changes are dominant,
20
10
Focal, mild
I
I
I
I
10 No.of patients
OXY- &,
philic group 0
4
I
4
Mixed 0 group 0
FIGURE 10. Number of patients with hyperthyroidism (solid bars), euthyroidism (dotted bars), latent hypothyroidism (striped bars), and overt hypothyroidism (open bars) in each histologic group in 19 children with chronic thyroiditis. Parentheses indicate number of patients exhibiting each thyroid function.
sometimes showing hyperthyroidism. In the present study the distribution of the childhood cases classified into each histologic type was similar to that in the adult cases and, functionally, these childhood cases showed various classifications: latent hypothyroidism in the oxyphilic type, hyperthyroidism in the mixed type, and euthyroidism in the focal type. Stromal fibrosis was rarely seen in these cases in our study. Recently, some interesting clinical entities, such as postpartum transient hypothyroidism” or silent (painless) thyroiditis, 25.26have been reported. Both diseases are functionally transient and self-limited, and usually treatment against hyperthyroidism or hypothyroidism is unnecessary. Documentation of the histolo ‘c appearance of both diseases is extremely limited, *P but a precise histologic examination of the thyroid gland from these patients may be useful in the elucidation of the pathogenesis of the disease. We reported that in silent thyroiditis, showing transient hyperthyroidism or hypothyroidism, the thyroid gland shows a unique histologic feature representing marked follicular destruction and a histologic resolution of the lesion in the course of the disease.‘* In summary, we report that our histologic classification of chronic thyroiditis might be useful in predicting the thyroid function of patients. Thyroid needle biopsy should be recommended as a useful and safe tool not only for the evaluation of thyroid function in patients with chronic thyroiditis, but also for the determination of causes of hyperthyroidism or hypothyroidism.
ically4,‘”
I
(Mizukami et al)
30 % I
.~_~.~_~_~_~_~_~.~.~.~.~.~.~.~.~ .~.~.~.~.~,~.~.~,~,~.~.~.~,~,~.~ , ', 0 .~.~.~.~.~_~.~.~.~_~,~,~,~,..~,~ .
Acknowledgment.
assistance
script.
and Yasuko
The authors thank Sanae Itoh for typing Kamei for preparation of the manu-
REFERENCES FIGURE 9. Frequency of patients with latent hypothyroid function in the histologic focal group in association with extent of cell intiltration (mild, moderate, and marked).
1. Doniach D, Roitt IM: Autoimmune thyroid disease, in Miescher PA, Muller-Eberhard HJ (eds): Textbook of Immunopathology. New York, NY, Grune & Stratton, 1976, pp 715-735
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HUMAN PATHOLOGY
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1992)
1.1. Takahashi K. Nakagawa 51, Midol-ikawa 0: Histologic picture oI Hashitoxicosis. Clin Endocrinol (Tokyo) 26: 1251-l 255. 197X (in ,Japanese) 15. Fatourechi V. McConahey WM. Woolner- 1.B: Hypel-thyroidism associated with histologic Hashimoto’s thyroiditis. Mayo (:lin PI-oc 46:682-6X9, 1971 16. Mizukami I’, Matsubara F: Clinicopathological study on natural course of chronic thyroiditis. .Jpn J Clin Pathol 26:602, 1978 (suppl) (in Japanese) 17. Mizukami Y, Funaki N, Hashimoto T, et al: Histologic features of thyroid gland in a patient with bromide-induced hypothyroidism. Am J Clin Pathol 89:802-805, 1988 18. Mizukami Y, Michigishi T. Nonomura A. et al: Iodine-induced hypothyroidism-A clinical and histologic study of 28 patients. J Clin Endocrinol Metab (in press) 19. Greenberg AH, Czernichow P, Hung W. et al: Juvenile chronic lymphocytic thyroiditis: Clinical, laboratory and histological correlations. J Clin Endocrinol Metab 30:293-301, 1970 20. Nilsson 1.R: Adolescent colloid goiter. Acta Paediatr Stand 55:49-63. 1966 2 1. Hung W: Goiters in euthyroid adolescents, in Heald FP, Hung W (eds): Adolescent Endocrinology. New York, NY, Appleton-CenturyCrofts, 1970, pp 79-99 22. Rallison ML, Dobyns BM, Keating FR, et al: Occurrence and natural history of chronic lymphocytic thyroiditis in childhood. .J Pediatr 86:675-682, 1975 23. MiienpHi J, Raatikka M, R%inen J, et al: Natural course of juvenile autoimmune thyroiditis. J Pediatr 107:898-904, 1985 24. Amino N, Miyai K, Km-o R, et al: Transient postpartum hypothyroidism: Fourteen cases with autoimmune thyroiditis. Ann Intern Med 87:155-159. 1977 25. Woolf PD, Daly R: Thvrotoxicosis with painless thyroiditis. Am J Met! 60:73-79, 1976 ‘26. Papapetrou PD. Jackson IMD: Thyrotoxicosis due to “silent” thyroiditis. Lancet 1:361-363. 1975
2. Hazard JB: Thyroiditis. A review. Part II. Am J Clin Pathol 25:399-426. 19.55 3. Woolner LB, McConahey WM. Beahrs OH: Struma lymphomatosa (Hashimoto’s thyroiditis) and related thyroidal disorders. J Clin Endocrinol 19:53-83, 1959 4. LiVolsi VA: Lymphocytes in the thyroid, in Surgical Pathology of the Thyroid. Philadelphia, PA, Saunders, 1990, pp 68-97 5. Sato ‘I’. Takata 1, Taketani T. et al: Concurrence of Graves’ disease and Hashimoto’s thyroiditis. Arch Dis Child 52:951-955, 1977 6. Takeda R, Nakabayashi H, Kawato M, et al: Clinical value of the thyrotropin-releasing hormone stimulation test in predicting mild hypothyroid state in chronic thyroiditis. Endokrinologie 65: 171-l 76, 1975 7. Kawato M: Functional and pathohistological correlation of the thyroid and chronological outcome in chronic focal thyroiditis. Folia Endocrinol Jpn 55:887-903, 1979 8. Mizukami Y, Matsubara F: Clinicopathological study on the chronic thyroiditis and Graves’ disease-Relationship between histological classification and function. Nippon Naika Gakkai Zasshi 69: 321-329, 1980 9. Hawk WA, Crile G, Jr, Hazard JB. et al: Needle biopsy of the thyroid gland. Surg Gynecol Obstet 122:1053-1065, 1966 10. LiVolsi VA: Cytology and needle biopsy, in Surgical Pathology of the Thyroid. Philadelphia. PA, Saunders, 1990, pp 367-384 11. Mizukami Y, Matsubara F: An enzyme histochemistry and electron microscopic study of chronic thyroiditis and Graves’ disease. Nippon Naibunpi Gakkai Zasshi 56:241-250, 1980 12. Mizukami Y, Michigishi T, Hashimoto T, et al: Silent thyroiditis: A histologic and immunohistochemical study. HUM PATHOI. 19:4?3-431. 1988 13. Means JH, DeGroot LJ, Stanbury JB: Chronic thyroiditis, in The Thyroid and Its Diseases (ed 3). New York, NY, McGraw-Hill, 1963, pp 433-461
988
YUJI MIZUKAMI, MD, TAKATOSHI MICHIGISHI, MD, MASANORI KAWATO, MD, TAMOTSU SATO, MD, AKITAKA NONOMURA, MD, TAKUMA HASHIMOTO, AND FUJITSUGU MATSUBARA, MD Six hundred one patients with histologically proven “chronic thy roiditis” were assessed for the correlation of thyroid function to histologic findings. The histology of chronic thyroiditis was classified $to four groups (oxyphilic, mixed, focal, and hyperplastic), and the thyroid function of patients was divided into hyperthyroid, euthyroid, latent hypothyroid, and overt hypothyroid, based on the laboratory data of serum triiodothyronine (T3), thyroxine (T4), and thyrotropin (TSH) levels, as well as thyrotropin-releasing hormone (TRH) tests. In the oxyphilic group (137 cases), 116 (85%) of the patients were classified as hypothyroid: 52 (38%) as latent hypothyroid and 64 (47%) as overt hypothyroid. In the mixed group (161 cases), the thyroid function of the patientsvaried. Thirty-seven(23%) of the patientswere classifiedas hyperthyroid,61(39%) as euthyroid, 54 (33%) as latent hypothyroid, and nine (5%) as overt hypothyroid. In this group thyroid function was intimately related to the ratio of replacement by hyperplastic-changed follicles and oxyphilicchanged follicles. In the focal group (149 cases), 123 (83%) of the patients were classified as euthyroid, while 22 (14%) were classified as latent hypothyroid. The frequency of latent hypothyroid patients increased in parallel with the severity of cell infiltration. In the byperplastic group (154 cases), 130 (85%) of the patients were classified as hyperthyroid. In this series 19 patients under 10 years of age were included, and no difference in the distributionof histologic varietieswas observed betweenjuvenile and adult patients. Thyroid needle biopsy is a useful and safe tool, not only for the histologic diagnosis of chronic thyroiditis,but also for the evaluationof thyroid function and the identification of causes for hyperthyroidism or hypothyroidism. Hm PATHOL 23:980-988. Copyright 0 1992 by W.B. Saunders Company
Histologic features of the thyroid gland in patients with “chronic thyroiditis” are considerably varied and reveal a broad spectrum. Several histologic classifications of chronic thyroiditis have been proposed, such as the Doniach and Roitt classification,’ the Hazard classification,” the classification of Woolner et a1,3 and the LiVolsi classification.” However, few large-scale studies have focused on the correlation between thyroid func-
MD,
tion and histologic findings of chronic thyroiditis. Such attempts have been made by pathologists and endocrinologists. It used to be thought that extrapolation of functions from the histologic appearance of thyroid gland is too inconsistent for clinical purposes.
From 1975 to 1980 at Kanazawa University Hospital (Kanazawa, Japan), an extensive clinical and pathologic exploration project on chronic thyroiditis was carried out. In this project frequency of patients, physical findings of patients, detailed thyroid function state, circulating thyroid antibodies, and histologic changes of thyroid gland corresponding with these clinical data were examined by both endocrinologists and pathologists. 5-7 At that time most of these findings, especially the histologic findings of the thyroid gland in this disease, were not sufficiently clarified. We are now reviewing the clinical and histologic data obtained during the project and are convinced that these data on chronic thyroiditis, especially the data on thyroid function and histologic findings of thyroid gland, will provide a meaningful basis for a comparison between clinical status and histologic findings in chronic thyroiditis. Most of the patients (430 patients) were included in an earlier report* that was written in Japanese. The current report deals with the original study’s 430 patients and 171 additional patients.
MATERIALS
AND METHODS
Six hundred one patients from Kanazawa University Hospital between 1975 and 1980 were included in this study. Patients were chosen because they had thyroid biopsies with histologic evidence of mononuclear cell infiltration. The patients who underwent large needle biopsy of the thyroid gland were limited to those presenting with findings of both a diffuse goiter of various degrees and positive circulating thyroid antibodies (ie, those clinically diagnosed as having chronic thyroiditis). Patients with typical Graves’ hyperthyroidism or with simple goiter were excluded from the needle biopsy examination. In most cases sera were obtained from untreated patients in the month prior to biopsy and stored at -20°C until determination, but in a few cases referred to us from other hospitals propylthiouracl or methimazole treatment for hyperthyroidism had been performed. Also, in a few patients with florid toxic symptoms biopsies were performed after 1 month of propylthiouracil or methimazole administration. Patients with transient hyperthyroidism or hypothyroidism, sug-
From the Pathology Section, Departments of Nuclear Medicine. Internal Medicine, Laboratory Medicine, and Pediatrics, Kanazawa University Hospital, Kanazawa, Japan. Accepted for publication March 4,1991. Kq words: thyroid needle biopsy, chronic thyroiditis, histologic classification, thyroid function, thyrotropin-releasing hormone test. Address correspondence and reprint requests to Yuji Mizukami, MD, Pathology Section, Kanazawa University Hospital, 13-1, Takaramachi, Kanazawa, 9‘20. Japan. Copyright 0 1992 by W.B. Saunders Company 0046-8177/92/2X)9-0003$5.00/O
980
CHRONIC THYROIDITIS:
TABLE
FUNCTION
AND HISTOLOGY
1. Evaluation of Thyroid Function Serum Level of T3 and T4
Thyroid Function Hyperthyroid
High
Euthyroid
Normal range T3: 88-177 ng/dL T4: 6.3-13.5 pg/ dL Normal - low normal Low
Latent hypothyroid Overt hypothyroid
Pathologic Examination
TRH Test No - low response ATSH: <5 pU/mL Normal response ATSH: 5-29 pU/mL Exaggerated response ATSH: 30-85 pU/mL Exaggerated response ATSH: >85 pU/mL.
Note: ATSH, the value of increased thyrotropin to thyrotropinreleasing hormone.
gesting postpartum hypothyroidism or silent (painless) thyroiditis, were excluded from this study. Of the 601 patients, 545 underwent a large needle biopsy using a Silverman’s needle. Needle biopsy specimens were obtained from both thyroid lobes in most cases; however, in a few cases sufficient specimens for diagnosis were obtained from only one thyroid lobe. Our colleagues (endocrinologists) were well experienced in the procedure of large needle biopsy, and all biopsies were safely carried out with the patient’s approval and with no complications. The remaining 56 patients underwent surgical biopsies. Serum thyroxine (T4) was measured by competitive protein-binding analysis with a Tetrasorb-125 kit (Abbott Laboratories, Abbott Park, IL). The normal range was 6.3 to 13.5 pg/dL. Serum triiodothyronine (T3) was determined by radioimmunoassay. The normal range was 88 to 177 ng/dL. Serum thyrotropin (TSH) was measured by radioimmunoassay using the double antibody method. The thyrotropin-releasing hormone (TRH) stimulation test was carried out by intravenous injection of 500 PcLg TRH (Tanabe Pharmaceutical Co, Osaka, Japan) and serum for the TSH assay was drawn before and at 20, 40, 60, and 90 minutes after the administration of TRH. The normal range of basal TSH was less than 5 pU/mL, and the increased TSH to TRH (ATSH) ratio was 5 to 29 pU/mL. On the basis of the T3, T4, basal TSH level, and increased TSH to TRH ratio, at least four groups could be distinguished as follows: hyperthyroid, euthyroid, latent hypothyroid, and overt hypothyroid. The outlined criteria are presented in Table 1.
TABLE 2. Histologic Group
(Mizukami et al)
The thyroid specimens were divided into four histologic groups in terms of the replacement of both lymphocytic infiltration and altered follicular epithelium. Our classification was primarily based on Woolner et al’s classification of chronic thyroiditiss (Table 2). Chronic thyroiditis, oxyphilic. The thyroid gland shows a diffuse interfollicular infiltration of mononuclear cells and diffuse epithelial oxyphilic changes with mild to severe stromal fibrosis. Oxyphilic-changed epithelium has a swollen, oxyphilic, and granular cytoplasm. This group includes three subgroups of diffuse thyroiditis in Woolner et al’s classification’: diffuse thyroiditis with oxyphilic epithelium, pronounced epithelial destruction, and lymphoid type (Fig 1). Chronic thyroiditis, mixed. The thyroid specimen shows more or less diffuse infiltration of mononuclear cells and a mixture of altered follicular cells, composed of oxyphilic, hyperplastic, normal, and unclassified epithelial change. This group corresponds to Woolner et al’s subgroup of diffuse thyroiditis with varied epithelial changess (Fig 2). Chronic thyroiditis, focal. The thyroid specimen shows a focal or spotty collection of mononuclear cells and minimal changes in follicular epithelium or stromal fibrosis, corresponding to Woolner et al’s major group of focal thyroiditis.’ In this group the extent of cell infiltration was graded from mild to marked. Mild indicates a less than 10% loss of parenchyma by scattered collections of mononuclear cells, moderate indicates a 10% to 50% replacement by cell infiltration, and marked indicates a greater than 50% replacement (Fig 3). Chronic thyroiditis, hyperplastic. The specimen shows difluse hyperplastic changes of follicles. Follicular cells are cuboidal or slightly columnar and follicles show some irregularity in shape or some degree of papillary folding. Mononuclear cell infiltration is mild. This group includes Woolner et al’s subgroup of thyroiditis with hyperplastic epitheliums (Fig 4). In addition to the histologic classification of the oxyphilic, mixed, focal, and hyperplastic groups in 601 cases, the percentage of loss of parenchyma by fibrosis was evaluated in each case of the oxyphilic group, and the ratio of replacement by each follicular epithelial change (oxyphilic, hyperplastic, normal, and unclassified) was evaluated in each case of the mixed group. Statistical analysis was performed using Student’s t-test. Differences were judged to be significant at a confidence level greater than 95% (P < .05).
Histologic Classification
of Chronic Thyroiditis
Histologic Findings
Chronic thyroiditis, oxyphilic
Diffuse cell infiltration: moderate to severe Oxyphilic epithelial changes: almost all Fibrosis: mild to severe
Chronic thyroiditis, mixed
Diffuse cell infiltration: moderate Follicular epithelial changes: various (oxyphilic, hyperplastic, and normal) Fibrosis: minimal to mild
Chronic tbyroiditis, focal Mild Moderate Marked Chronic thyroiditis, hyperplastic
Focal cell infiltration Extent of cell infiltration
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Corresponding Diffuse thyroiditis, Diffuse thyroiditis, Diffuse thyroiditis, destruction Diffuse thyroiditis,
Woolner’s
Classification
oxyphilic epithelium lymphoid type pronounced epithelial varied epithelial changes
Focal thyroiditis
Thyroiditis with “hyperplastic”
epithelium
HUMAN PATHOLOGY
Volume 23, No. 9 (September
1992)
FIGURE 1. Oxyphilic group. (Left) Diffuse heavy interfollicular infiltration of mononuclear cells and diffuse epithelial oxyphilia are observed. (Hematoxylin-eosin stain; magnification X78.) (Right) Extensive stromal fibrosis with follicular atrophy is predominant. (Hematoxylin-eosin stain; magnification X78.)
RESULTS Clinical Findings The age and sex distribution of the 601 patients is shown in Fig 5. Five hundred forty-seven patients were female and 54 were male (female to male ratio, 10: 1). Five hundred thirty-four (89%) of the 60 1 patients were between 20 and 60 years of age; 19 patients were under 10 years of age and 48 were over 61 years of age. The median age of all patients was 37.9 years. In relation to the histologic groups the median age of the patients was highest in the oxyphilic group (44.3 years) and, in descending order, mixed group (37.7 years), focal group (37.4 years), and hyperplastic group (32.9 years). The percentage of the cases of the oxyphilic group increased in accordance with aging. On the other hand, the percentage of cases of the hyperplastic group decreased after 40 years of age (Table 3). Correlation of Thyroid Function of Patients to Their Histologic Groups The distribution of all patients by histologic group, thyroid function, and age is shown in Table 3 and Fig
6. In the oxyphilic group, 116 (85%) of 137 patients were hypothyroid. Fifty-two (38%) patients were latent hypothyroid and 64 (47%) were overt hypothyroid. Only four (3%) patients were hyperthyroid and 17 (12%) patients were euthyroid. In this group the relationship between the thyroid function or age of the patients and the extent of stromal fibrosis in their thyroid specimens was examined in 89 patients from whom sufficient thyroid specimens were obtained for this evaluation (Fig 7). There was a correlation found between the age of the patients and the extent of fibrosis in the thyroid specimens from 49 patients with overt hypothyroidism (r = .518). This finding suggested that in younger patients hypothyroidism might be caused by the involvement of thyroid hormone synthesis in the oxyphilic changed epithelium while, on the other hand, in older patients increased stromal fibrosis generally accompanied hypothyroidism. In the mixed group, 37 (23%) of the 161 patients were hyperthyroid, 61 (39%) euthyroid, and 54 (33%) latent hypothyroid. Only nine patients were overt hypothyroid. For quantitative histologic evaluation, to
FIGURE 2. Mixed group. (Left) Diffuse interfollicular infiltration and variously changed epithelium composed of oxyphilic, hyperplastic, and normal epithelium are observed. (Hematoxylin-eosin stain; magnification X100.) (Right) Higher magnification discloses oxyphilic (0). hyperplastic (h), and normal (n) epithelium. (Hematoxylin-eosin stain; magnification x400.)
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CHRONIC THYROIDITIS:
FUNCTION
AND HISTOLOGY
(Mizukami et al)
FIGURE 3. (Top left) Focal, mild group. Focal lymphocytic infiltration is observed in a normal-appearing background. The extent of replacement by cell infiltration is less than 10%. (Hematoxylin-eosin stain; magnification x3 1.) (Top right) Focal, moderate group. The extent of cell infiltration is from 10% to 50%. (Hematoxylin-eosin stain; magnification X31.) (Bottom) Focal, marked group. The extent of cell infiltration is more than 50%. (Hematoxylin-eosin stain; magnification x31 .)
clarify the relationship between the histologic appearance and the thyroid function of the patients in this group, the altered follicular epithelium was classified into the following four types: hyperplastic, oxyphilic, normal, and unclassified. The mean amounts of replaced area by each type of altered follicular epithelium were estimated in each specimen. The results were as follows. In thyroid specimens from patients of the hyperthyroid
group the mean value of replacement by hyperplastic epithelium was approximately 37%, whereas that by oxyphilic epithelium was 29%. On the other hand, in the latent hypothyroid group the mean value of replacement by hyperplastic epithelium markedly decreased to 3%, and that by oxyphilic epithelium increased to 62% (Fig 8). This finding indicated that the thyroid function of patients in the mixed group was closely related to the composition ratio of hyperplastic-changed epithelium and oxyphilic-changed epithelium in their thyroid specimens. In the focal group, 123 (83%) of the 149 patients were euthyroid, three (2%) were hyperthyroid, and 22 (14%) were latent hypothyroid. Only one patient was overt hypothyroid. In relation to the extent of cell infiltration (mild, moderate, and marked), the frequency of latent hypothyroid patients increased in accordance with the enlargement of the area of cell infiltration from mild to marked: 7% of patients in subgroup mild, 15% in moderate, and 26% in marked. The difference was significant: P < .05 (Table 4 and Fig 9). The median ages of patients in the focal group increased as follows: mild (36.9 years), moderate (37.3 years), and marked (37.5 years). In the hyperplastic group, 130 (85%) of the 154 patients were hyperthyroid, eight were euthyroid, five were latent hypothyroid, and 11 were overt hypothyroid. Most of these 24 euthyroid or hypothyroid patients had
FIGURE 4. Hyperplastic group. Diffusely hyperplastic epithelial changes and mildly focal lymphocytic infiltration are observed. (Hematoxylin-eosin stain; magnification x100.)
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HUMAN PATHOLOGY
Volume 23, No. 9 (September
1992)
110 100 [
0
FIGURE 5. Sex and age distribution of 601 patients with chronic thyroiditis. hundred forty-seven pati%t: are female (open bars) and 54 are male (shaded bars). The number above each column indicates the number of oatients.
3s
L 3
:::.
0 - 10
11
-a,
31 - 40
21 - 30
51 - 60
41 - 50
We
been treated with propylthiouracil the time of their serum sampling. Chronic Thyroiditis
or methimazole
at
11 - a0
J.0.
DISCUSSION Since 1950, hormonal and immunologic studies of chronic thyroiditis have progressed extensively, and the diagnosis and evaluation of the functional state in patients with chronic thyroiditis have been relatively easily carried out. At the same time, histologic examination of the thyroid gland using the large needle biopsy method also has been routinely performed for histologic diagnosis of chronic thyroiditis. In our hospital, not only fine needle aspiration biopsy of the thyroid gland, but also large needle biopsy, which yields a histologic specimen, have been used successfully and safely by physicians since 1972 for the diagnosis of thyroid disease.
in Childhood
Thyroid specimens from the 19 patients under 10 years of age who were considered to be in the earlier stage of the disease were also divided histologically into oxyphilic, mixed, focal, and hyperplastic groups. In the oxyphilic group four of five patients were latent hypothyroid and in the mixed group all four patients were hyperthyroid. In the focal group all three patients were euthyroid and in the hyperplastic group all seven patients were hyperthyroid (Table 3 and Fig 10).
TABLE 3.
61 - 10
I
2
Functional Distribution of 601 Patients With Chronic Thyroiditis
by Histologic Group and Patient Age
Age (yr) Total Histologic
Group
1 l-20
21-30
31-40
41-50
51-60
61-70
5 1
5 1
21 1
18 5
28 4
39 3
Hyperthyroid Latent hypothyroid Overt hypothyroid
0 4 0
0
0
I
8
3
12
3 4 6
0 8 16
Mixed (total) Euthyl-oid Hyperthyroid Latent hypothyroid Overt hypothyroid
4 0 4 0 0
27 8 10 9 0
19 5 6 5 3
34 17 5 10 2
Focal (total) Euthyroid Hyperthyroid Latent hypothyroid Overt hypothyroid
3 3 0 0 0
26 25 1 0 0
23 17 1 5 0
Hyperplastic (total) Euthyroid Hyperthyroid Latent hypothyroid Overt hypothyroid
7 0 7 0 0
24 1 23 0 0
46 2 37 3 4
Oxyphilic (total) Euthyroid
Note: Data are expressed
O-10
as number
of patients
71-80
(%)
17 2
4 0
137 17 (12)
0 17 19
0 10 5
1 0 3
4 (3) 52 (38) 64 (47)
38 19 4 13 2
28 9 5 13 1
10 3 3 3 1
1 0 0 1 0
161 61 37 54 9
(39) (23) (33) (5)
25 20 0 5 0
38 31 1 6 0
22 16 0 5 1
10 9 0 1 0
2 2 0 0 0
149 123 3 22 1
(83) (2) (14) (1)
31 3 26 1 1
14 1 12 0
28 1 22 1 4
2 0 1 0 1
2 0 2 0 0
154 8 130 5 11
(5) (85) (3) (7)
in each category.
984
I
CHRONIC THYROIDITIS:
FUNCTION
AND HISTOLOGY
(Mizukami et al)
FIGURE 6. Frequency of patients with hyperthyroid (solid bars), euthyroid (dotted bars), latent hypothyroid (striped bars), and overt hypothyroid (open bars) in each histologic group (oxyphilic, mixed, focal, and hyperplastic). Parentheses indicate percentage of patients exhibiting each thyroid function. riyperplastic group (154 w.ses
Large needle biopsy is a safe and accurate method to make a tissue diagnosis of chronic thyroiditis as well as nodular lesions. Based on a large number of cases (625 needle biopsies), Hawk et al9 reported that struma lymphomatosa lesions are suitable for large needle biopsy. In her recent textbook on the surgical pathology of the thyroid gland, LiVolsi” explains that morphologic diagnosis of thyroiditis can be more readily established with this technique. At present, when doing a histologic examination of the thyroid gland, pathologists are required not only to make a histologic diagnosis of chronic thyroiditis, but also to evaluate the thyroid function of the patient or to confer with the clinician concerning the treatment of the patient. However, few histologic studies have been
reported that place emphasis on detailed thyroid function in patients with chronic thyroiditis. Therefore, in this study we attempted to elucidate the correlations between thyroid function and thyroid histology in patients with chronic thyroiditis from the standpoint of a re-evaluation of Woolner et al’s classification of chronic thyroiditis3 We believe that the data described here provide a foundation for interpretation of morphologic changes in chronic thyroiditis in relation to thyroid function. Diffuse and more extensive mononuclear cell infiltration and uniform oxyphilic epithelial changes were characteristic histologic features of thyroid specimens in the oxyphilic group. Our previous enzyme histochemical study” showed that these oxyphilic-changed epithelia are lacking in the activity of peroxidase, an essential enzyme for the biosynthesis of thyroid hormone. Therefore, it is understandable that the majority of patients in the oxyphilic group were hypothyroid. A decrease of thyroid parenchyma due to stromal fibrosis is also an important contributing factor, and an increase in the extent of stromal fibrosis was associated with aging of the patients. Recently, hypothyroidism has been classified into two groups in view of its clinical course: reversible and irreversible hypothyroidism. The distinction of these types is sometimes difficult from analysis of clinical and laboratory data. The thyroid gland in patients with transient, reversible hypothyroidism usually reveals the histologic features of the mixed type of chronic thyroiditis in our classification, or chronic thyroiditis with extensive follicular destruction as described in our previous study of “silent thyroiditis.“” On the other hand, a thyroid gland revealing irreversible hypothyroidism shows a pronounced epithelial exyphilla and stromal fibrosis of various degrees. We consider thyroid needle biopsy to be a useful and key diagnostic tool in the differentiation of both types of hypothyroidism. In the mixed group, thyroid function of patients was dependent on the composition ratio of replacement by
. .
FIGURE 7. Relationship between thyroid function, age of patients, and extent of fibrosis in thyroid specimens in the histologic oxyphilic group. In 49 patients with overt hypothyroidism, a correlation between patients’ ages and extent of fibrosis is observed (y = 0.5x - 3.6; r = 518). Open circles, euthyroid patients; open triangles, latent hypothyroid patients; solid circles, overt hypothyroid patients.
985
HUMAN PATHOLOGY
Volume 23, No. 9 (September
20
40
60
80
I
I
I
I
1992)
100
% I
FIGURE 8. Mean percentage of replacement by oxyphilic (small-dotted bars), hyperplastic (striped bars), normal (large-dotted bars), and unclassified (open bars) follicular changes in thyroid specimens from patients of the histologic mixed group. Numbers indicate mean percentoges of replacement.
Ayperthyroid patients
(n=37)
Euthyroid patients
(n=bl)
-.__
La tent
-.
‘\
*. . S. 27 ‘\ 62 ‘_‘.‘_‘.‘.‘.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.’.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~...~.....~.~,~,~.~.~.~,‘,~.‘.‘.‘.‘.~. hypOthyro
i
d
ll l l l l
::i:i:i:i:_:i:i:i:::i:::::i:i:i:i:i:i:i:-:::-:-:::::::~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:i:::_:::i:i:::~:::~:i:i:i:::~~
f
........_.................................................... . . . . . . . . . . . . . . . . . .._................_.................. ~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~,~.~.~..,..~.~.~.~.~.~.~,~.~.~.~.~.~.~.~ _.... ....~.~.~.~.~_~.~.~.~.~.~.~.~.~. •.“.v.v.~ ‘.~.‘.‘.‘.~.‘.‘.‘.‘.‘.~.‘.‘.‘.‘.~.’.’.’.’.’.~.~.~.‘.‘.~.‘.~.’.~.‘.~.‘.~.‘.~.‘.‘.~.~.~.~,~,~.’,’.‘.~.~.~.~.‘.‘.‘.‘.‘. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .._........... eeeae
patients (n= 54)
~..........................~..............._................
hyperplastic- and oxyphilic-changed epithelium. Patients with thyroid gland revealing more than 40% replacement by hyperplastic-changed epithelium were usually in a hyperthyroid state. On the other hand, thyroid specimens from hypothyroid patients showed an increased rate of replacement (mean, 62%) by oxyphilic-changed epithelium and a markedly decreased rate of replacement (mean, 3%) by hyperplastic-changed epithelium. “Hashitoxicosis,” a term proposed by Means et al,‘” has been regarded as a clinical entity of concurrent chronic thyroiditis and Graves’ disease. Histologic criteria for hashitoxicosis are controversial.‘4.‘5 Fatourechi et alI5 defined this disorder as hyperthyroidism with the pathologic features of Hashimoto’s disease. Based on our present study, we would like to propose three histologic criteria for hashitoxicosis: the patient is in a hyperthyroid state, the thyroid specimen from the patient is classified as belonging to the mixed group, and the thyroid specimen reveals more than 50% replacement by hyperplastic-changed epithelium. For the other histologic characteristics of the mixed group, the changes in the ratio of replacement by hy-
TABLE 4.
Functional
perplastic- or oxyphilic-changed epithelium in thyroid specimens are not infrequently observed in association with functional alteration of patients during a relatively short period (several months). We have encountered such a condition by follow-up thyroid biopsies.“j Such a histologic and functional alteration may be observed more frequently after a few weeks of treatment, especially in patients receiving treatment with antithyroid drugs against hyperthyroidism, and, subsequently, patients may develop hypothyroidism. Careful attention should be paid to the treatment of the hyperthyroid patients whose thyroid is histologically classified as belonging to the mixed group. In the focal group, most patients have been thought to be euthyroid. However, Takeda et al6 reported that 47% of the patients with focal thyroiditis showed an exaggerated response to TRH. In our study, 14% of the patients in the focal group were latent hypothyroid. Furthermore, in relation to the subgroups, 7% of the patients in subgroup mild, 15% in moderate, and 26% in marked were latent hypothyroid. Therefore, there was a tendency toward an increase in the frequency of
Distribution of 149 Patients With Focal Thyroiditis of Cell Infiltration (Mild to Marked) and Patient
(Focal Aae
Group)
by Extent
Age tyr) O-10
1 l-20
Mild (total) Euthyroid Hyperthyroid Latent hypothyroid Overt hypothyroid
1 1 0 0 0
Moderate (total) Euthyroid Hyperthyroid Latent hypothyroid Overt hypothyroid
2 2 0 0 0
Marked (total) Euthyroid Hyperthyroid Latent hypothyroid Overt hypothyroid Note: Data are expressed
as number
21-30
31-40
41-50
51-60
10 10 0 0 0
10 8 1 1 0
9 8 0 1 0
10 10 0 0 0
9 8 1 0 0
10 7 0 3 0
12 11 0 1 0
7 7
3 2
0 0
01 0
of patients
61-70
71-80
Total (%)
7 5 0 2 0
5 5 0 0 0
1 1 0 0 0
53 48 (91)
19 14 1 4 0
10 7 0 2 1
2 2 0 0 0
1 1 0 0 0
65 52 (80) 2 (3) 10 (15)
4 1
9 7
5 4
3 2
31 23 (74)
03 0
20 0
01 0
01 0
: (26) 0
in each category.
986
1 (2) 4 (71 0
1 (2)
CHRONIC
THYROIDITIS:
FUNCTION
AND HISTOLOGY
5
patients with latent hypothyroidism in accordance with an increase in the extent of cell infiltration. In the hyperplastic group, the great majority of patients were hyperthyroid. Eight patients were euthyroid and 16 patients were hypothyroid, but most of these 24 patients were under propylthiouracil or methimazole treatment. We have previously reported histologic changes (an increase in the extent of cell infiltration and follicular epithelial degeneration) in Graves’ thyroids after long-term treatment with antithyroid drugs.” In the present study the histologic picture of the thyroid gland from these euthyroid or hypothyroid patients after treatment showed a relatively heavy focal cell infiltration, a disappearance of hyperplastic changed epithelium, and an increase of degenerated epithelium showing a swollen, vacuolated, or eosinophilic granular cytoplasm. Consequently, it was difficult to histologically distinguish the hyperplastic group from the mixed group. In addition, a pronounced hyperplastic change of the thyroid gland might be observed in patients with iodine-induced hypothyroidism associated with chronic thyroiditis. Our earlier studies”*‘” dealing with bromine-induced and iodine-induced hypothyroidism disclosed that the thyroid gland in both diseases shows characteristic histologic changes, not only extensive hyperplastic changes but also clear and vesicular cytoplasmic change of follicular cells and depletion of colloid material in the follicular lumen. In iodine-induced hypothyroidism, only restriction of excess intake of dietary iodine readily restored euthyroidism. Attention should be paid to hypothyroid patients whose thyroid is histologically classified as belonging to the hyperplastic group. In recent years chronic thyroiditis has been recognized as a common cause of goiter in children.1g-23 In our study 19 childhood cases were observed. The clinical and pathologic analyses of these cases may be interesting from the viewpoint of the clarification of the natural course of chronic thyroiditis. It has been generally considered that focal thyroiditis is an earlier stage of chronic thyroiditis and that diffuse thyroiditis is a later stage of the disease. However, our study indicated that both focal and diffuse types of chronic thyroiditis might develop independently earlier in life. The juvenile form of chronic thyroiditis has been considered by some investigators to differ from the other types pathologbecause follicular oxyphilia is usually mild or absent, but hyperplastic epithelial changes are dominant,
20
10
Focal, mild
I
I
I
I
10 No.of patients
OXY- &,
philic group 0
4
I
4
Mixed 0 group 0
FIGURE 10. Number of patients with hyperthyroidism (solid bars), euthyroidism (dotted bars), latent hypothyroidism (striped bars), and overt hypothyroidism (open bars) in each histologic group in 19 children with chronic thyroiditis. Parentheses indicate number of patients exhibiting each thyroid function.
sometimes showing hyperthyroidism. In the present study the distribution of the childhood cases classified into each histologic type was similar to that in the adult cases and, functionally, these childhood cases showed various classifications: latent hypothyroidism in the oxyphilic type, hyperthyroidism in the mixed type, and euthyroidism in the focal type. Stromal fibrosis was rarely seen in these cases in our study. Recently, some interesting clinical entities, such as postpartum transient hypothyroidism” or silent (painless) thyroiditis, 25.26have been reported. Both diseases are functionally transient and self-limited, and usually treatment against hyperthyroidism or hypothyroidism is unnecessary. Documentation of the histolo ‘c appearance of both diseases is extremely limited, *P but a precise histologic examination of the thyroid gland from these patients may be useful in the elucidation of the pathogenesis of the disease. We reported that in silent thyroiditis, showing transient hyperthyroidism or hypothyroidism, the thyroid gland shows a unique histologic feature representing marked follicular destruction and a histologic resolution of the lesion in the course of the disease.‘* In summary, we report that our histologic classification of chronic thyroiditis might be useful in predicting the thyroid function of patients. Thyroid needle biopsy should be recommended as a useful and safe tool not only for the evaluation of thyroid function in patients with chronic thyroiditis, but also for the determination of causes of hyperthyroidism or hypothyroidism.
ically4,‘”
I
(Mizukami et al)
30 % I
.~_~.~_~_~_~_~_~.~.~.~.~.~.~.~.~ .~.~.~.~.~,~.~.~,~,~.~.~.~,~,~.~ , ', 0 .~.~.~.~.~_~.~.~.~_~,~,~,~,..~,~ .
Acknowledgment.
assistance
script.
and Yasuko
The authors thank Sanae Itoh for typing Kamei for preparation of the manu-
REFERENCES FIGURE 9. Frequency of patients with latent hypothyroid function in the histologic focal group in association with extent of cell intiltration (mild, moderate, and marked).
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