THYROIDITIS: A REVIEW
PART II
J O H N B. HAZARD, M.D.
Department
of Pathology, The Cleveland Clinic Foundation, and The Frank E.
Educational Institute, Cleveland, Ohio
Bunts
IV. T H Y R O I D I T I S O F U N D E T E R M I N E D ETIOLOGY
A. Subacute (Granulomatous) Thyroiditis
Subacute thyroiditis is a nonsuppurative inflammation of the thyroid gland
characterized by acute onset, subacute or chronic course, local pain, tenderness
and usually mild fever. Pertinent histologic features are acute and subacute
inflammation, fibrosis and a granulomatous (pseudotuberculous) reaction in
the gland.
The synonyms for the disease are: de Quervain's thyroiditis, granulomatous
thyroiditis, •pseudotuberculous thyroiditis, giant-cell thyroiditis, creeping thyroiditis,
struma granulomatosa, struma fibrosa—giant-cell variant, acute noninfectious
thyroiditis and acute nonsuppurative thyroiditis. In recent writings the disease
most commonly is referred to as subacute thyroiditis. This is an appropriate
designation since the earliest phase of the malady seldom is seen by the physician.
Historical Note
The disease was studied first in 1904 by de Quervain,39 who later, in 1935
with Giordanengo,40 clearly separated it from other forms of thyroiditis. In the
American literature, Jaff676 appears to be the first to indicate a nontuberculous
etiology, regarding the tubercle-like structures as the result of noninfectious
involutionary changes. In 1948, Crile24 emphasized the fact that the clinical
entity then recognized as subacute thyroiditis is histopathologically identical
with pseudotuberculous thyroiditis.
Incidence
The incidence of subacute thyroiditis cannot be determined with accuracy
because the disease often has been confused with acute infectious nonsuppurative thyroiditis, with tuberculosis, and even with Riedel's struma. Furthermore, certain cases may remain unrecognized.
Giordanengo65 in 1938 stated that only 54 cases had been reported since de
Quervain's original study in 1904. Crile and Rumsey29 suggested that many
cases have been unrecognized clinically, and cite the experience at the Cleveland
Received for publication September 13, 1954; accepted, November 22, 1954. T h e first
part of this review was published in Volume 25, No. 3 (March, 1955), p p . 289-29S.
Dr. Hazard is Pathologist.
Review articles in the Journal are under the direction of E . A. Gall, M . D . , Cincinnati
General Hospital, Cincinnati 29, Ohio.
399
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HAZARD
Vol. 25
Clinic where 38 cases were seen in the 3 years, 1946 through 1948, whereas only
27 had been recognized in the preceding 10 years. Lindsay and Dailey95 reported
no change in incidence. Crile25 and Stalker and Walther134 regard the disease as
the most common type of thyroiditis.
The disease occurs predominantly in women, the ratios of women to men being
4:1 t o 6 : l . 2 9 ' 9 5
The patients are nearly always adults and are in the 30 to 50 year age group,
but ages may range from 23 to 71 years. 29 ' 50 ' 95 ' 125,134
Crile24 found 17 cases in 900 goiters, approximating 2 per cent; only 2 of the
patients came to operation. The operative incidence for the series of Lindsay
and Dailey96 was 0.31 per cent but these authors noted that since 1944 most
of the patients had been treated medically.
The recorded incidence of the disease as compared to that of other types of
thyroiditis shows a wide variation. Crile24 regards the disease as being 5 times
as common as both struma lymphomatosa and struma fibrosa (Riedel) combined. Lindsay and Dailey,95 however, find subacute thyroiditis to be about 10
times as frequent as Riedel's struma, and one tenth as common as struma
lymphomatosa, the percentages regarding thyroidectomies being 0.31, 0.027
and 3.0, respectively. In the series of Marshall, Meissner and Smith,96 group I
thyroiditis, apparently the subacute variety, comprised a little more than one
fifth of the entire operative series of chronic thyroiditis.
Etiology and Pathogenesis
The etiology is unproved. Routine cultures have been negative.95 A vims
etiology has been suggested, 24 ' 50 ' 134 and is supported by the high incidence of
associated upper respiratory infection.29' 134 Lindsay and Dailey95 were unable
to demonstrate inclusion bodies. Schilling125 believes that the disease is due to
the effect on the thyroid gland of bacterial infection of the throat and nasal
passages and injury by bacterial toxins. Stalker and Walther134 regard the
proximity of infected tonsils as playing some role. Recently the possibility of a
reaction of hypersensitivity has been suggested by Lindsay and Dailey.95 Crile24
observed an unusual reaction in one patient with subacute thyroiditis to an
undulant-fever skin test, manifested by increased pain and tenderness in the
thyroid. At present, opinion favors the possibility of a viral etiology but so far
as can be determined no studies to establish such an agent have been made.
DeCourcy 35-37 regards "Riedel's disease" as caused by perithyroiditis, but
from the descriptions the designation would appear to refer to the subacute type
of thyroiditis. There is no association with other thyroid disease.94
The pathogenesis of the granulomatous reaction has received some consideration also. Jaff676 considered it definitely noninfectious. Crile24 regarded it as
being a reaction of wandering cells to colloid. This view is supported by the
work of Ferguson,48 who produced a foreign-body reaction by injecting extracts
and residues of human colloid subcutaneously into guinea pigs. Just as in subacute thyroiditis, there was little evidence of necrosis and a proliferation of
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THYROIDITIS
401
fibroblasts. Chesky, Dreese and Hellwig15 ascribe the reactions in chronic thyroiditis to an altered colloid but do not specifically indicate subacute thyroiditis.
Radioiodine studies support the view that the thyroid gland does not take up
or bind iodine in the normal manner.67 Fraser and Harrison50 compare the
changes in gland function with those of the normal person taking an antithyroid
drug; the capacity to form thyroid hormone is blocked, but there is no impairment of its release. They believe that this dysfunction is due to an agent, probably a virus, within the follicular epithelium, which may be dispelled by thiouracil, since the administration of methylthioiiracil restored the ability of the
thyroid gland to accumulate radioiodine. Because the disease begins in a normal
gland with approximately 2 months' store of preformed hormone, blood levels
of the latter remain normal or elevated due to increased absorption from damaged follicles.29' 50 Robbins and his associates120 suggest that the low radioiodineconcentrating capacity of the thyroid gland is due to the action of the high level
of serum protein-bound iodine (PBI), directly on the thyroid gland or via the
pituitary gland or a depression of pituitary activity by the infection itself. They
found transient restoration of radioiodine uptake toward normal after administration of thyrotrophin. Lindsay and Dailey,95 noting flattened and apparently inactive follicular epithelium, suggest that this may indicate decreased
pituitary activity.
Clinical Features
Clinically, there often is an acute onset of sore throat, severe pain on swallowing, and sudden pain and tenderness in the thyroid gland. 29,95 The onset may
be fulminating but usually is mild, or it may be chronic.26' M There often is
radiation of pain to the ear and occasionally to the face, jaw or occiput on the
affected side. 29,96 This radiation of pain may be the dominant symptom and
lead to erroneous diagnosis. Some patients though fully aware of the sore throat
or pain in other areas are not conscious of thyroid involvement. 12 ' 29 Rarely, as
seen in the late phases of the disease, there may be little or no tenderness, but
only a sensation of choking and pressure due to the hard enlargement,26 simulating carcinoma.
Lindsay and Dailey95 found prodromal fever and sore throat preceding the
onset of pain in some cases. A low-grade fever may persist throughout the
course of the disease even when prolonged. Occasionally the fever may be as
high as 104 F.29 Fatigue, weakness and lassitude are prominent constitutional
symptoms, and occasionally there are chills and night sweats.29 Usually the
symptoms are sufficiently mild to permit the patient to carry on ordinary
activities, but in a few instances the severity of exhaustion, weakness, and
toxicity require hospitalization.134 Hyperthyroidism may be present.95
Local pressure symptoms are not prominent but have been observed after
several months, and Lindsay and Dailey95 record 1 case of tracheal obstruction.
The thyroid gland is firm or rubbery to palpation, and usually diffusely but
not markedly enlarged. 29 ' 95, 134 Tenderness usually is marked, often is sharply
localized. The disease was unilateral in 20 per cent of Crile and Rumsey's29
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HAZARD
Vol. 25
cases. As the disease continues, the pain and tenderness commonly may migrate elsewhere in the gland (creeping thyroiditis). 24 ' 29,95 ' 134 In chronic cases
the tenderness may be absent29 and the gland be of hard consistence.
There usually is no history of precedent goiter. 29 ' 95
The differential diagnoses, clinically, are: acute infectious thyroiditis, hemorrhage into an adenoma, and hyperthyroidism in the acute phase; nodular goiter,
adenoma, and carcinoma in later phases. 29 ' 95 ' 134 The differentiation from
malignant disease is especially difficult when there is little pain or tenderness.
Crile 25 ' 28 recommends needle biopsy to establish the diagnosis. Lindsay and
Dailey95 prefer surgical exploration and biopsy when a pathologic diagnosis is
necessary.
Clinical Laboratory Findings
The sedimentation rate consistently is elevated. 24,26,29, 50 ' 95 ' 134 Crile and
Rumsey29 found no elevation of the white cell count; Lindsay and Dailey95
recorded leukocytosis as infrequent and without relation to the clinical severity
of the disease. Robbins and his associates12 record a slight elevation of lymphocytes in some patients. The basal metabolic rate usually is within normal
limits, 29 ' 95 but may be above plus 10, and as high as 28 per cent. 2 9 ' 9 5 '" The
plasma cholesterol usually is normal or may be below normal. 50 ' 120
Of specific interest are the levels of serum protein-bound iodine and thyroidal
radioiodine accumulation. Subacute thyroiditis, in the active phase, is unique
in that there is a strikingly negligible uptake of radioiodine,29' 6 0 ' 6 7 ' 9 5 ' 144 and
yet a definitely elevated or high normal serum protein-bound iodine (PBI). 50 ' 67'
95,120 Lindsay and his associates94 found that the levels of PBI generally ranged
from 9.7 to 11.6 micrograms.per cent, and in 1 case record a value of 26.0 micrograms per cent. Robbins and his associates,120 in 8 of 9 cases, found an uptake
of radioiodine at 48 hours of 2.3 per cent or less; McConahey and Keating99
record 24-hour values of 0 to 5.2 per cent usually, but with 2 of 13 cases showing higher levels than this. Crile and Rumsey29 found a depressed accumulation
of radioiodine, even when only one lobe was involved clinically. As the inflammatory process in the gland resolves, the values for protein-bound iodine return
to normal, usually in 3 to 4 weeks after treatment and the uptake of radioiodine
also becomes normal, usually in 2 to 3 months.67
Pathologic Anatomy
At operation some degree of perithyroiditis is frequent; Lindsay and Dailey
found the majority of the glands adherent to the trachea and adjacent muscles.95
The capsule always is intact, so that the gland may be cleanly shelled out with
minimum difficulty. This one feature distinguishes the lesion from Riedel's
struma in which the perithyroid tissues are inseparably incorporated with the
thyroid mass.
The gland is slightly or moderately enlarged and may be 2 or 3 times its
normal size. Its outlines are preserved. Fine tags of fibrous tissue may be observed on the capsular surface but there is no adherent muscle. The surfaces
are of smooth contour, generally, though occasionally there may be a few bos-
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THYROIDITIS
403
selations.95 The involved areas are pale, avascular, firm, rubbery or hard, tough,
and may comprise the entire gland or occur as localized areas usually several
centimeters in diameter.
On section, the firm white or yellow-white tissue of the involved areas is in
sharp contrast to any normal thyroid tissue that may remain. However, such
zones shade into the uninvolved tissue rather than being separated by a sharp
line of demarcation. The altered tissue is of avascular appearance, resilient,
tough, and may be gritty on section. A delicate or coarse trabeclilation is present. There are no zones of necrosis and nodules are seldom seen.24'94
The microscopic features include follicular degeneration, variable fibrous replacement, and an infiltration of leukocytes, lymphocytes and plasma cells. 29,95
Distinctive, however, is the presence of groups of histiocytes and giant cells
producing a tuberculoid appearance. The lesions are of focal nature 94 and in
affected portions of the gland several or many more lobules are involved in their
entirety. The early phase is characterized by acute degeneration of the follicular
epithelium, desquamation of cells in the acini, and active inflammatory changes;
later phases are dominated by the granulomatous pattern and fibrosis. A variation in the stage of reaction frequently is found within the same gland94 or in
the same thyroid lobe; the pseudotuberculous lesion has been observed early28
and its presence makes it possible to diagnose the disease soon after onset.
Follicular abnormalities consist of a change in the epithelium to cuboidal type,
variable degrees of degeneration and necrosis, and loss of colloid.95'125 Rarely
an extravasated mass of colloid is observed in the perifollicular stroma. Caseous
necrosis never is seen. A leukocytic infiltrate is present in the edematous stroma,
in the degenerating epithelial layer and in follicular lumens. Microabscesses
occasionally are seen. Eosinophils may be present in large number.95 Though
lymphocytes and plasma cells are found, they never dominate the histologic
picture and lymph follicle formation is unusual.
The most helpful indication of the identity of the lesion is the presence of
histiocytes and their frequently focal and tubercle-like arrangement. Because
of follicular degeneration, it is not always possible to determine the relation of
granulomatous lesions to the follicles, but they may be found both interstitially
and within the follicles. In addition, foreign-body giant cells are present in
variable number, both in association with and separate from the histiocytes.
At times, an irregular mass of colloid is found centrally in a group of these
mononuclear and multinucleate phagocytes, and occasionally there may be an
intracytoplasmic mass of this material in a giant cell.
Fibroblastic proliferation and fibrous replacement are prominent features
and furnish the background for much of the exudative changes described above.
Early, there is edema and mucoid change;95 later, there is an increase in density
and eventually fibrous replacement of severely involved areas.
Healing is featured by proliferation of the follicular epithelium94 and regeneration of those follicles in which epithelial elements remain, disappearance of the
giant cells and most of the other exudative elements, and variable degrees of
fibrous repair. A nonspecific chronic inflammatory reaction may persist for
some time.94
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HAZARD
Vol. 25
In areas of thyroid parenchyma not specifically involved in the process follicles are unchanged. Lindsay and Dailey95 have found the epithelial cells in
these areas to be flat and apparently inactive.
The capsule always is retained but often shows slight thickening and some
inflammatory reaction.95
There may be slight inflammation of vessel walls, intimal thickening, and
obliteration of lumens. Lindsay and Dailey95 regard these as secondary to the
inflammation of the gland, and as changes associated with the patient's age.
Radioautographic studies of 1 case by Lindsay and Dailey96 revealed no uptake of radioiodine in the damaged areas; in the normal or larger regenerated
follicles containing colloid there was some accumulation but this was regarded
as less than normal.
The macroscopic differential diagnosis of most concern regards the focal
lesion of subacute thyroiditis and papillary carcinoma. The latter may present
white areas resembling fibrosis, and, if the tumor is not of particularly papuliferous type, the true nature of the lesion may not be readily apparent. The
neoplasm, however, is more sharply demarcated from the tissue of normal
character and often has a yellow-tan tinge. At times the differential diagnosis
can .be resolved only by microscopic examination and requires frozen section
for immediate diagnosis. Because of the extensive fibrosis found in some glands
with subacute thyroiditis, there has been confusion with struma fibrosa (Riedel);
however, the well-defined and well-preserved capsule serves definitely to exclude
the latter disease. Furthermore, in most cases the granulomatous pattern of
subacute thyroiditis is distinctive. The fibrolymphoid variant of struma lymphomatosa reveals no tubercles, an abundance of lymphocytes, oxyphilic epithelium
and retention in some degree of lobulation, even in severely involved areas. The
fibrocaseous type of tuberculosis is excluded by the absence of areas of necrosis
and the miliary type by the marked fibroplasia and paucity of lymphocytes.
The histologic features of subacute thyroiditis usually are sufficiently distinctive for diagnosis by needle biopsy.29
Treatment
Recent reports favor the use of cortisone or ACTH. 16 ' so. 32,74,78,85, 143 p r e v i _
ously, external radiation was recommended, 29,95, l07 but was not accepted
with enthusiasm by some.134 Thiouracil and its derivatives have received support. 13 ' 5 0 , 8 0 Antibiotics and chemotherapeutic agents and iodine administration are without value. 50,95, 134 Radioiodine therapy is not effective.85
Surgical intervention by subtotal thyroidectomy has been employed, but such
treatment is usually reserved for those patients in whom medical therapy has
failed or when carcinoma is suspected.96 Crile24 reports persistence of symptoms
or later involvement of the other lobe following simple lobectomy.
Course
Subacute thyroiditis is principally a self-limited disease. 24,50,126 Usually it
persists no longer than 1 to 3 months, 95 although there may be recurrence after
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THYROIDITIS
405
this time or continuance of the disease for a year or more.134 Generally there is
no subsequent derangement of function,24, 134 but hypothyroidism has been observed after thyroidectomy.96
B. Struma Lymphomatosa
The disorder is characterized by an insidious onset with enlargement of the
thyroid, most frequently the entire gland, and the development of pressure
symptoms. It occurs predominantly in women. The basic morphologic alterations are enlargement and oxyphilia of the follicular cells, and lymphoid infiltration, with or without interstitial fibrosis.
Synonyms are: Hashimoto's struma, lymphadenoid goiter, chronic lymphoid
thyroiditis.
The disease was first described by Hashimoto, 68 in 1912, in a report based
on his observations of 4 patients, all women over 40 years of age. He recorded
the clinical and pathologic characteristics of the disorder in considerable detail,
and considered the malady entirely distinct from previously reported diseases
of the thyroid gland, including the thyroiditis recorded by Riedel. In 1922,
Ewing,47 on the basis of a study of 4 cases of thyroiditis, concluded that the
disorder described by Riedel was merely a later stage of Hashimoto's struma.
Graham and McCullagh,63 and Graham 59 after a study of the literature and
their own cases concluded in 1931 that these maladies were separate clinicopathologic entities.
Incidence
59
Graham found 16 cases, which he regarded as authentic, published previous
to 1929. Craig, Spann and Lowbeer23 found 563 cases reported from 1912 to
1951. Since that report there have been several large series added to the literature. In 1951, Statland, Wasserman and Vickery,135 reported 51 cases; Lindsay,
Dailey, Friedlander, Yee and Soley,94 170 cases in 1952; and Furr and Crile53
62 cases in 1954.
Blake and Sturgeon6 found no relation between incidence and social status.
Nearly all patients have been women, the percentages varying from 90.463 to
100135 in the various clinical series. Blake and Sturgeon 6 found 9 cases in males
reported in the literature prior to 1953.
The disease is commonest in the fourth and fifth decades, and the reported
mean or average values usually lie between 40 and 45 years,108, 135 although the
figure of 31.7 years is reported by Lindsay and his associates,94 and 49.2 years
by McClintock and Wright.98 The age range is wide, 73^86 to 78s8 years in the
various reports. Schilling125 advises scrutiny of the diagnosis in a girl or in a
male. Since lymphocytic thyroiditis now is a well-recognized entity in young
people and may histologically simulate struma lymphomatosa, his reluctance
to accept the diagnoses of cases in the youthful age group as being true Hashimoto's struma is fully justified.
The incidence among thyroidal operations has been stated variously as
ranging from 0.31 to 3.3 per cent. 6, "• 9 4 , 9 6 , 1 3 5
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HAZARD
Vol. 25
Relative to Riedel's thyroiditis, struma lymphomatosa is reported as 4 times136
to nearly 100 times94 as frequent.
No definite geographic distribution has been established.94, 135
The determination of the prevalence of struma lymphomatosa is beset with
certain difficulties of diagnostic interpretation. The inclusion of Riedel's struma
and of lymphocytic thyroiditis would cause little alteration in the number of
cases reported, but the incorporation of instances of the frequently occurring,
nonspecific, lymphocytic infiltration of the thyroid gland would provide a
higher incidence than actually exists.
Etiology and Pathogenesis
The cause of the disease is obscure. It is agreed generally that it is not an
infection, and probably is metabolic in origin.94 The possibility that the malady
is a general constitutional disorder, of which the thyroid lesion is but a local
manifestation, has been suggested by Graham 59 and .Toll.77 Davison and Letton34
noted that each one of their patients had had an emotional upset preceding
onset of the goiter, and they noted also a marked increase in the number of
cases they had seen in recent years. They thought that possibly the anxiety
and constant unrest during the years of World War II might have produced
chronic stimulation of the thyroid gland.
The possible role of hyperfunction of the thyroid gland in pathogenesis has
been given much consideration. There is some morphologic support in the frequent occurrence of thyroidal lymphocytic infiltration in hyperthyroidism, active or in remission and, in addition, the presence of focal oxyphilic change in
the so-called "burned out" toxic goiter. Lindsay and his associates94 stress the
frequency of the basic lesions of Hashimoto's disease in involuting hyperplastic
and nodular goiters. Lennox91 states that the oxyphilic (Askanazy) cells do not
secrete thyroxin, and that their appearance must be regarded as a regressive
phenomenon, possibly as a "worked out" hyperplastic gland. Graham and
McCullagh63 found no preceding symptoms that would be regarded as toxic,
but believed that if such could be found in the past history, the basic reason
for the changes in the thyroid in struma lymphomatosa would have been discovered. Davison and Letton,34 and Levitt92 favor a theory of transition from
the hyperthyroid state through one that is euthyroid, and then hypothyroid.
Polowe,113 Lee and McGrath, 87 Vaux,138 Eden and Trotter, 43 McSwain and
Moore,101 and Lindsay and his co-workers94 have reported cases in which hyperthyrodism was evident in the presence of disease that they regarded as struma
lymphomatosa. Joll77 was in disagreement with the inclusion of certain cases by
Vaux1-38 as early struma lymphomatosa with hyperthyroidism, regarding them
instead as instances of lymphocytic infiltration in toxic goiter. Until there
is agreement on the criteria for sharp separation of Hashimoto's disease from
this group, the controversy cannot be resolved. I t is difficult to justify inclusion
of a case with obvious hyperthyroidism in the group of Hashimoto's struma
merely because of the presence of lymphocytic infiltration or of minimal focal
oxyphilia.
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THYROIDITIS
407
Parmley and Hellwig108 were impressed with the high incidence of menstrual
irregularities among their patients. They suggested that loss of ovarian function,
causing pituitary overactivity, might bear some relationship to pathogenesis.
Lindsay and his associates,94 however, found no definite experimental indication
that either excess of, or deficiency in, ovarian hormones produces the disease.
Statland and his associates135 note that the disease may occur in normally
menstruating women.
Changes in the thyroidal epithelium have been emphasized as being of basic
importance. 59,77,108 ' 135 Graham 60 regarded them as degenerative and believed
that the fibrosis is a result of damage to the epithelial cells, comparable to that
found in cirrhosis and nephrosclerosis. Lennox91 noted that Askanazy (Hiirthle)
cells were frequent in thyrotoxic goiters, and in older women; infrequent in nontoxic glands, and in men. He questions whether the epithelial change is not
merely an altered activity of the thyroid gland in older women. Lindsay and his
associates94 regard the epithelial changes as involutionary and call attention to
Friedman's 52 conception of follicular involution. They suggest that administration of desiccated thyroid is effective therapy because it reduces the demand
on thyroid epithelium. Parmley and Hellwig108 propose that the hyperplastic
changes in the epithelial cells are compensatory to the exhaustion of thyroid
hormone in a goiter that has lost its faculty to manufacture colloid.
Williamson and Pearce146 attribute the lymphoid infiltration to production
of an abnormal amount of a lymphogenic substance by the thyroid gland. Goldberg and Davson67 regard lymphoid infiltration as an exaggeration of that
occurring in toxic goiter. Furr and Crile63 suggest that there may be a decrease
in the production of effective lymphoid-moderating hormones. Chesky and his
associates16 account for the lymphocytic infiltration on the basis of colloidophagy
of altered colloid within the follicles. The macrophages, re-entering the stroma,
disintegrate and deposit the altered colloid in the stroma, where it acts as an
irritant focus for lymphocytic infiltration. Hellwig,70 using the electron microscope, had previously noted a difference in the shape of the particles of colloid
in thyroiditis as compared with those of the normal secretion.
Several suggestions have been made regarding the possible relationship of
thyrotrophic hormone. Parmley and Hellwig108 suggested that the normal thyroid cycle was interrupted by hyperactivity of the hypophysis following the loss
of ovarian function, as previously stated. Chesky, Dreese and Hellwig15 explain
colloidophagy on the basis of alteration of the colloid through the effect of
thyrotrophic hormone. Furr and Crile53 speculate that the disease may be the
result of an increased thyrotrophic-hormone production by the pituitary gland,
or a decrease in lymphoid-regulating hormone, and-believe that the effective
action of desiccated thyroid either is through depression of the former hormone
or through changes in production of the latter. Lindsay and his associates94
note that in Graves' disease with prolonged stimulation by thyrotrophic hormone, there is exhaustion of the follicular cells. A neutralizing effect of lymphocytes on thyroid-stimulating hormone is suggested by the work of Rawson,
Sterne and Aub,115 who found that exposure of pituitary extract to thymic or
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HAZARD
Vol. 25
lymph node tissue removed thyrotrophs substance. Bastenie3 noted lymphocytic
infiltration of the thyroid gland in guinea pigs that had been administered
pituitary extract. Though these findings are to be considered in a discussion of
possible relationships, Statland and his associates135 remark that no evidence of
increased thyrotropic activity has been encountered in early cases of struma
lymphomatosa. Lindsay and his associates94 similarly note no evidence of exophthalmos or lymphocytosis unless there is frank hyperthyroidism.
Prolonged iodine administration has been suggested as having a possible
etiologic relationship, but many patients with struma lymphomatosa, including
those of Hashimoto, have not received such medication.135 Lennox91 found no
relation between the oxyphilia of thyroid epithelium and iodine administration.
Regarding iodine lack, Lindsay and his associates94 found no correlation between
prevalence of struma lymphomatosa and residence in endemic areas. They
believe it likely, however, that the epithelial exhaustion follows hyperplasia
unassociated with production of thyroid hormone and that it may be due to
absolute or to relative lack of iodine. These authors further call attention to the
cellular changes seen in adolescent goiter that are due to iodine deficiency, and
that closely resemble those of Hashimoto's struma.
A vitamin deficiency was suggested by the experimental work of McCarrison ,97
He reported lymphoid infiltration in the thyroid gland, fibrosis and atrophy of
the glands of rats that had been on a vitamin-deficient diet 2}/% to 6 months.
This work has not been directly corroborated; Rinehart119 found no lesions like
those of Hashimoto's struma in animals on diets deficient in many vitamins. No
clinical relationship to vitamin deficiency has been recorded in the human
disease.135
Recently, Clausen,17 by prolonged administration of thiouracil, produced, in
the thyroid glands of rats, changes similar to those of struma lymphomatosa,
including marked lymphocytic infiltration, fibrosis and follicular degeneration.
Among the studies reviewed, the following aspects are regarded as of especial
interest in relation to pathogenesis: (a) excessive involutionary change, idiopathic or following mild or subclinical hyperthyroidism (b) effect of prolonged
administration of thyrotrophs hormone (c) experimental production of a
lymphoid type of goiter by protracted thiouracil administration.
Clinical Features
The commonest complaints are goiter or fullness in the throat. Pressure
symptoms predominate but usually are mild or moderate. 94 ' 126 ' 135'14V Dysphagia
is common.94 The systemic complaints are vague, such as a lack of a feeling of
well being, nervousness and fatigue.24, 5 3 ' 7 7 ' 1 0 8 ' 1 2 5 , 1 3 5 Hoarseness and dysphonia
may occur with the more solid goiters. 6 ' 77 ' 89 Furr and Crile53 found that the
majority of patients with hoarseness had a pathologic condition of the vocal
cords. Lindsay and his associates94 found the fibrous variant of struma lymphomatosa in some patients with constricting glands. The onset of the goiter usually
is insidious24 and is not noted before pressure symptoms appear.77 About one
half of the patients have noted the goiter a year or less94 •136 and rarely the gland
April 1955
THYROIDITIS
409
may reach considerable bulk within a few weeks or months. 28 ' 77 Twelve per cent
of the patients in Furr and Crile's series53 had a goiter for 20 years or more.
Hypometabolism or myxedema preoperatively is uncommon, occurring in 10
per cent or less of cases.53, 6 3 , 9 0 ' 9 6 , 135 Hyperthyroidism or hypermetabolism
has been recorded by some; 34,87,94, 113,138 in one of the most recent reports it was
stated as occurring with an incidence of 12 per cent of the series.94
In many patients there is absence or abnormality of menses,108 but Statland
and his associates136 regard this condition merely as a correlation with the age
group concerned.
Furr and Crile63 note a frequent association with other ailments, chiefly
anxiety state, but most patients reveal little evidence of previous serious ill
health. 77,135 A history of precedent thyroidal enlargement is unusual, except
where goiter is endemic.77 Pregnancy is not a precipitating factor.53
The thyroid gland usually is diffusely enlarged 2 to 5 times normal size, firm
to rubbery, hard but not iron-hard. 6,77,125,135 Commonly, there is some prominence of the isthmus and the poles may be blunt. 6 Occasionally there may be
disparity in the size of the lobes, and the pyramidal lobe may be prominent.94
Thirty-two per cent of the series reported by Furr and Crile53 showed asymmetry
of the gland. The surface usually is smoothly lobular,77 but may be nodular.53
Some degree of tracheal fixation may be present but adherence never is a prominent feature.125
Though pain is not generally a symptom, 6 tenderness has been encountered in
15 per cent or less of the patients. 2 4 , 9 0 , 9 4 , 109,126, 135 No point of maximum tenderness is mentioned, such as is found in subacute thyroiditis.
There is no exophthalmos, no fever,24 and rarely elevation of pulse rate.108
Clinically there are several differential diagnoses of importance. When tenderness is a factor, subacute thyroiditis is to be excluded. Nodular goiter may be
suggested by exceptionally prominent bosselations;26 an asymmetrical enlargement, or prominence of the pyramidal lobe, may be mistaken for adenoma. The
unusually firm consistence of some glands may cause concern regarding carcinoma. Crile26 recommends confirmation of diagnosis by needle biopsy. Recent
implications regarding an appreciable incidence of carcinoma in association with
struma lymphomatosa have led to some theoretical considerations of reluctance
for such an approach to diagnosis. 6,94
Clinical Laboratory Findings
The routine urine and blood examinations usually have been reported as
revealing no significant change, but anemia and white-blood-cell counts of less
than 6000 per cu. mm. were present in an appreciable number of cases of the
series of Furr and Crile.53 Lindsay and his associates94 found no lymphocytosis;
McSwain and Moore101 report that it may be slight and relative. The sedimentation rate may be elevated.53 Furr and Crile53 record achlorhydria in 5 of 9 cases
studied, a finding that is in agreement with Graham's earlier observation.60
Statland and his associates135 found that the blood cholesterol levels varied from
141 to 326 milligrams per cent. Little is recorded concerning studies on blood
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HAZARD
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protein. Cooke and Wilder22 report abnormal serum colloidal-gold tests with
curves of the order of 555554 and 555410.
The serum protein-bound iodine values generally are in the hypothyroid
range. In 3 cases, Statland and his associates135 record them as 0.9 to 4.4 micrograms per cent. No values for the butanol extractable fraction have been noted.
The basal metabolic rate is recorded by Lehman and Maiden90 as low normal
in approximately one half the patients. Furr and Crile53 found values of zero or
below in 80 per cent of cases. Statland and his associates135 record a range of
minus 33 to plus 16; only 1 in the series of 51 cases was of the highest value and
this patient was euthyroid. An almost identical range is reported by Blake and
Sturgeon. 6 McConahey and Keating" found normal values the rule and a mean
initial value of minus 9.8 plus-or-minus 2.7 per cent. High basal metabolic rates
have been recorded by some authors, but whether such cases can be included as
true Hashimoto's disease is a matter of debate.
The radioiodine accumulation usually is normal.53 McConahey and Keating"
found values normal in most patients despite the fact that one third were regarded as myxedematous. Two of 11 patients had levels too low to measure,
yet, interestingly, were not in the myxedema group.
Pathologic Anatomy
The gland is 2 to 5 times normal size and usually is diffusely enlarged and
often symmetrical;94 occasionally it is asymmetrical 53 - 94 due to prominence of a
lateral lobe or of the pyramidal lobe.94 When there is asymmetry, the right lobe
often is larger than the left.94 Frequently there is mild adherence to the trachea
and cervical structures, especially with the fibrous variant.94 The capsule often
is slightly thickened but always is distinct and well preserved. Retrotracheal
extension may occur and rarely the trachea may be almost or completely encircled.6, 94 ' 106,125 The surface configuration generally is regular, but it may be
smoothly lobulated, bosselated or nodular. 94 ' 125,136
The surgical specimens of thyroid tissue vary in weight from 24 to 225
Gm. l08- 135 with reported averages of 45.7 Cm.108 to 66.8 Gm.135 Generally, the
gland is of paler color than usual and is of firm and often rubbery consistence.94'9<J
The sectioned surface is moist, avascular, often lobulated, bulging, with irregular
islands of pink, pale-tan, light gray-brown, gray-white, or yellowish tissue,
separated' by slightly depressed, and widened white, fibrous interlobular septums. 6 , 9 4 , 147 The tissue may be unusually friable due to lymphoid overgrowth.
Involvement of a lobe or only a portion of a lobe has been reported for about 10
per cent of cases.94 Occasionally, there is a nodular configuration. The uncommon
fibrous variant, forming 12 per cent of the series of Lindsay and his co-workers,94
is of hard, fibrous consistence and presents a homogeneous, smooth, slightly
bulging, gray-white or white cut surface, with indistinct or absent lobulations.
Adenomas are inconspicuous,60 but the variation in the prominence and size of
the thyroid lobules may produce a resemblance to nodular goiter or indicate
transformation of such a goiter. Colloid-containing tissue always is diminished
and may be absent.94
April 1955
THYROIDITIS
411
Histologically, there are 2 extremes of change: (1) a dense lymphocytic infiltration with little increase in fibrous stroma; and (2) predominence of fibrosis.
Between these extremes are many variations of the lymphoid-fibrous ratio.
There always is, however, a retention of a lobular pattern, although this may be
only faintly evident in those glands with severe degrees of fibrosis.
Regardless of the degree of stromal change or lymphoid infiltration, the most
characteristic and significant feature is found in the alteration of epithelium 60, "• 94, 10S to a distinctly oxyphilic type, with cells often larger than
normal, with abundant cytoplasm, and with nuclei that may be hyperchromatic,
and of variable size and shape. These may be of such bizarre appearance as to
suggest neoplastic alteration. Though the oxyphilic cells predominate, there
may be areas of paler staining epithelial cells of larger than usual size and with
granular cytoplasm. In shape, these cells are cuboidal, tall columnar or polyhedral.
In regard to the other 2 histologic features, lymphoid tissue and fibrous tissue,
the lesions may be divided into 3 general groupings: (1) Those in which lymphoid
tissue predominates, (the lymphoid variant); (2) Those with abundant fibrous
tissue (fibrous variant); and (3) Those with a balanced increase in both lymphoid
and fibrous tissues (fibro-lymphoid variant). The lymphoid infiltrate characteristically is diffuse,77,94,135 usually widespread, and consists principally of lymphocytes, but frequently includes plasma cells which may be numerous.94 A marked
lymphocytic infiltration is more common in rapidly enlarging goiters of short
duration. 63 Commonly, there are germinal centers. Rarely, these may be absent
and the infiltrate of a density to suggest lymphosarcoma. The lymphoid infiltration is present throughout the interstitial tissue, but it always is prominent in
the interfollicular zones, and may be less abundant in the interlobular stroma,
so that the highly cellular lobules appear rather sharply separated by the fibrous
trabeculae. Though diffusely distributed within the gland, the lymphoid tissue
varies in density and may be sparse or absent in areas. The lymphocytes and
plasma cells are of typical adult character and the lymph follicles are of usual
appearance. Parmley and Hellwig108 estimate that the lymphoid tissue comprises
about one third of the bulk of the gland.
An increase in fibrous tissue is a common feature but of variable degree. In
small amounts it may be inconspicuous and obscured by the lymphoid infiltrate
and the prominent epithelial change. Early, it is loosely arranged, but becomes
dense and hyaline as fibrosis progresses. The greatest accentuation is to be
found usually in the interlobular zone, where it may occur as broad fibrous
bands, isolating individual lobules. In approximately one tenth of glands, a
dense and abundant fibrosis throughout the thyroid gland occurs, but there
always is retention of lobular structure, even though this may be indistinct and
evident only as a few scattered small acini, or groups of individual epithelial
cells. The fibrous tissue often is of collagenous type and may be hyaline, or
keloid-like when there is most severe involvement.94 Regardless of the degree of
fibrosis, lymphoid infiltration always is present, though of variable amount.
The follicles classically are reduced in size and the lumens are small and oval.
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However, this change is not constant throughout the individual thyroid gland
and there are areas where the follicles are large, round or irregular, with a hyperplastic appearance. The prominent and characteristic feature, however, is the
presence of oxyphilic cells, larger than the usual follicular cell, throughout much
of the gland.
The colloid is diminished or absent in some follicles; in others it is homogeneous,
intensely staining,49 often with minimal peripheral vacuolation.
Large mononuclear cells and occasionally foreign-body giant cells are found in
follicular lumens, at times appearing to replace completely the colloid. Chesky,
Dreese and Hellwig15 by use of vital stains have identified these cells as macrophages rather than as desquamated epithelial cells.
Occasionally, in some fibrotic glands, there is a squamous change in the
epithelium evidenced by small solid islands of well-differentiated cells isolated
in abundant fibrous stroma.94
The vessels usually show no specific changes,8, "• 125 other than those of age.
Repeat biopsies over months or years have revealed relatively little change in
the character of the lesion.6' M ' 6 9 , 7 2 , 9 8 , 125 However, the reports are too sparse
and time elements mostly too short to permit generalization. Scarcello and
Goodale124 report an autopsied case as struma lymphomatosa, on the evidence
of lymphoid infiltration and oxyphilic epithelium in small thyroidal remnants
and state there had been a subtotal thyroidectomy 13 years previously. The
goiter, however, had been that of hyperthyroidism and the small germinal lesion
may not have been Hashimoto's struma.
There are a few reports of radioautographic studies after administration of
I131. Statland and his co-workers135 found an inconstant relation to the type of
epithelium in the few cases studied. Dempsey and his associates,38 from the
study of a gland with a 20 per cent 2-hour uptake, reported no evidence of
accumulation in regions of purely oxyphilic epithelium, but with radioiodine
concentration in the follicles with neutrophilic cuboidal cells.
Though the morphologic changes may be specifically stated, some believe
that a diagnosis cannot be made on pathologic findings alone. 6, 61 Certainly this
is true in borderline cases, and in the latter a diagnosis on minimal histologic
changes alone might lead to confusion. However, careful attention to the gross
as well as the microscopic appearance provides a high accuracy in diagnosis for
most specimens. When only a small tissue fragment is available for study, such
as a needle biopsy, it may be necessary to resort to a descriptive diagnosis, only
expressing compatibility with the disease entity. But even with such diminutive
tissue fragments it is possible to arrive at a correct diagnosis in a surprising
number of instances, provided that the characteristic epithelial change is
recognized.
The differential diagnoses are: malignant neoplasm, Riedel's struma, lymphocytic thyroiditis, nonspecific thyroiditis, and a miscellaneous group of those
glands associated with Addison's disease, primary myxedema, and so forth. The
gross examination is sufficient to exclude struma fibrosa (Riedel). The diffuse
thyroidal involvement and the regular lobular pattern are different from the
findings in most instances of carcinomas. Histopathologically, the nuclear atypia,
April 1955
THYROIDITIS
413
so common in oxyphilic epithelium, may be erroneously regarded as malignant.
However, the retention of a lobular pattern, and the absence or paucity of
mitoses serve further to differentiate the lesion from carcinoma. Seldom is the
infiltrate as uniformly diffuse as in lymphosarcoma; the presence of well-formed
lymph follicles serves as an absolute differential feature of the germinal center.
In the rare instance of diffuse lymphoid infiltration without lymph follicle
formation, differential features are the adult character of the lymphocytes, the
presence of plasma cells and the absence of subendothelial lymphocytic infiltration.41 Grossly, the capsule of the gland is universally retained in struma lymphomatosa, whereas in lymphosarcoma atypical lymphocytes frequently infiltrate
extracapsular tissues. The normal character of the germinal centers prevents
confusion with giant follicle lymphoma.
The changes in the thyroid gland in primary myxedema, adult cretinism,
hypopituitarism123 and thyroidal lymphoid infiltration in older and obese women76
simulate struma lymphomatosa, but there is no proliferation of stroma even
though it may be relatively increased, and, most important, the glands are small
or no greater than normal size. Similarly, in Addison's disease, especially when
it is due to cytotoxic degeneration of the adrenal cortex, the thyroidal histopathologic changes are somewhat like those in Hashimoto's disease but the
glands are typically small, weighing 8 to 17.1 Gm. in Sloper's series.131
Nonspecific thyroiditis and the group of diffuse goiters with lymphocytic
infiltration have offered difficulties in interpretation. Oxyphilia of the epithelium
seldom is found and when it does occur, as in so-called "exhaustion atrophy,"
it is minutely focal. Fibrosis is patchy and irregular.
The status of lymphocytic thyroiditis as a specific entity has not been definitely
established but, because of clinical differences and certain dissimilarities in blood
chemistry it seems desirable, for the present at least, to classify separately this
group of goiters in young people. The differential feature of importance is the
complete absence or the insignificance of oxyphilic epithelial change in the gland
of lymphocytic thyroiditis.
Treatment
53, 135
Roentgen therapy,
desiccated thyroid,53 cortisone26' 53 and combinations
53
of these have all been employed with some success. Slesinger130 has remarked
that desiccated thyroid medication is not effective in the late phase of the.
disease. Crile26 found struma lymphomatosa more resistant to thyroid therapy
than lymphocytic thyroiditis.
The recommendations for surgical treatment are conservative; partial bilateral
thyroidectomy,96 or excision of the isthmus,82 or of sufficient tissue otherwise to
prevent tracheal pressure. Womack147 advises against surgical extirpation unless
there are important obstructive symptoms. Recently the possibility of an associated carcinoma has been given as a reason for selection of surgical therapy. 6
Course
Characteristically, there is no spontaneous remission24 and, even after therapy,
restoration to health is slow.63 Hypothyroidism is common following operative
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HAZARD
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therapy, and mild myxedema may occur.34 Recurrence of goiter after subtotal
thyroidectomy is rare but has been recorded.6
There has been recent discussion regarding the occurrence of carcinoma in
struma lymphomatosa. Lindsay and his associates94 have recorded a prevalence
definitely higher in the Hashimoto type of thyroiditis than in other goiters. The
relationship of the disease and carcinoma is worthy of further study.
It has been suggested and reported that lymphoma of the thyroid gland
occasionally may originate in struma lymphomatosa.41 • M •79 •94 • 109 Statland and
his associates136 found no interpretable evidence in their series of cases to indicate such a relationship. Often a complete destruction of the gland prohibits
detailed study of any precedent lesion; furthermore, cases of thyroidal lymphoma
are too rare for adequate statistical evaluation.
C. Struma Fibrosa (Riedel)
This form of thyroiditis is evidenced by severe pressure symptoms resulting
from thyroidal enlargement and dense fixation to the cervical muscles and
trachea. The goiter often is unilateral and specifically is characterized by its
stony hardness. Pathologically, there is dense fibrous replacement of thyroid
tissue and extensive fibroblastic invasion of the adjoining soft tissues.
There are many synonyms but the more common are: Riedel's struma, Riedel's
thyroiditis, ligneous thyroiditis, woody thyroiditis, eisenharle strumitis, chronic
productive thyroiditis.
Historical Note
116
In 1896, Riedel described a rare type of thyroiditis that he had observed in
2 patients, a man of 42 years and a woman of 23. The goiters were of rather
rapid onset, of moderate dimensions, and accompanied by dyspnea out of
proportion to the degree of thyroid enlargement. The masses were extremely
hard and formed by chronic inflammatory tissue, characteristics that warranted
the descriptive title of the report "chronic inflammation leading to iron-hard
tumor of the thyroid." At operation, there was dense infiltration of the soft
tissues by the chronic inflammatory lesion, incorporating the trachea, nerves and
blood vessels, so that their successful liberation was not possible. He encountered
profuse bleeding and could only remove a small portion of tissue. Riedel's
second publication,117 in 1897, presented a third case in which the disease appeared in a man of 29. In 1910,118 he reported the benign course of this patient's
illness, following wedge resection of the thyroid isthmus, and further described
and summarized the character of the thyroiditis. The pertinent features were as
follows: A youthful age group, intense dyspnea, no evidence of infection, swelling
and hardening of the thyroid gland, rapid development of immature fibrous
tissue and massing of spindle and round cells between thyroid elements, and
incorporation of the trachea, nerves and blood vessels in the tumor-like mass,
so that excision of a thyroid lobe was completely impossible. He observed an
endarteritis, but believed that this was due to the chronic inflammatory process.
In 1885, 11 years before publication of the first of the articles mentioned
April 1955
THYROIDITIS
415
above, Bowlby8 gave a detailed description of a lesion of the thyroid gland, reported as infiltrating fibroma, which may correspond with the disease described
in the publications of Riedel.
Until 1912, many of the cases of chronic thyroiditis were recorded as belonging
to RiedePs group; after this date, when Hashimoto's publication68 appeared,
they were regarded as struma lymphomatosa. In 1922, Ewing47 expressed the
view that Hashimoto's struma was the earlier, and Riedel's thyroiditis the later
stage of the same disease. Nearly 10 years later, Graham and McCullagh63
clearly denned the 2 diseases, critically compared them and recommended their
recognition as separate entities.
Incidence
Struma fibrosa (Riedel) is of relatively rare occurrence. Graham 59 found 41
cases, which he regarded as authentic, reported in the literature through 1929.
.Toll77 encountered 5 cases in a series of previously unpublished cases of chronic
thyroiditis that included 81 instances of struma lymphomatosa. Lindsay and his
associates94 found Riedel's thyroiditis to be about 1 per cent of the incidence of
Hashimoto's disease. In regard to correlation to thyroid operations generally,
Levitt,92 in his tabulation of 94 cases, indicates an operative incidence of 0.03
per cent to 0.4 per cent. Joll77 found the operative incidence to be 0.14 per cent.
Recent reports of the disease have been sparse, in striking contradistinction to
the rapidly increasing literature regarding struma lymphomatosa.
The reported age incidence is variable and is regarded by some authors as
earlier than that for struma lymphomatosa. 54 ' 77 Eisen46 records the age limits of
published cases as 23 and 78 years, with 60 per cent of patients in the fourth and
fifth decades, but he may have included some instances of struma lymphomatosa.
Gilchrist54 reports the average age as 39 years. Crile24 reports a range of 42 to
74 years with an average of 51 years.
The occurrence rates in women and men have been reported as similar or
with a somewhat higher incidence in females, but this never is as high as that
found for struma lymphomatosa. 24 ' 44, 54' 58' 132
Difficulties are encountered in estimating the true prevalence of the disease,
since subacute (granulomatous) thyroiditis and the fibrous variant of struma
lymphomatosa have been reported as morphologically identical with struma
fibrosa (Riedel).
Etiology and Pathogenesis
Riedel's thyroiditis essentially is an inflammatory process primary in the
thyroid gland.59 The etiologic agent is unknown. DeCourcy35-37 has suggested
perithyroiditis with vascular injury as a cause, but his cases appear to have
been subacute thyroiditis rather than Riedel's struma. Meeker103 reported a
case in which spread of infection by way of the postbranchial system was indicated but, from the description, the reported lesion does not correspond with
that of true Riedel's thyroiditis. There is general agreement that the process is
inflammatory rather than a degenerative or involutionary change. However,
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HAZARD
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there is no specific explanation for the tumor-like proliferation by fibroblasts
that simulates a desmoid in its invasiveness and a keloid in denseness, yet is
characterized by an exudative reaction suggesting infection. In the reported
cases, no statement appears regarding any unusual propensity for fibroblastic
hyperplasia in other than the thyroid area.
Ewing's suggestion regarding the relationship of Riedel's struma to struma
lymphomatosa has been indicated previously. The weight of opinion now, however, favors these as separate and distinct entities. 6 ' 24 ' "• w ' 6 0 ' 6 3 ' 68, "• 8 7 ' 8 8 - 9 8 101, no, u2, 125,134,136 Womack147 includes both diseases in the designation chronic
degenerative thyroiditis. Those who believe that they are different stages of
morpholigic manifestations of the same process9•45•47• 126.146 have disregarded
the following features of Riedel's struma: it has been reported in a younger age
group, has a different sex distribution, and has many morphologic dissimilarities,
such as, (a) capsular destruction and extensive invasiveness of perithyroid
tissues; (b) a tendency to unilateral involvement of the thyroid gland; (c) the
lack of oxyphilic epithelium; (d) the absence of lymphocytic infiltrate in any
significant degree; (e) the presence of neutrophilic infiltration and even microabscess formation and (f) the involvement of wide areas of the thyroid gland
with complete loss of lobular structure. Furthermore, repeat biopsies or resections that have been performed in struma lymphomatosa have revealed little
change in the general morphologic character of the disease and no trend toward
struma fibrosa (Riedel). 6 ' 5 3 ' 6 9 ' 9 8 ' 125 Early in the controversy regarding relationship of the forms of thyroiditis, the rare fibrous variant of struma lymphomatosa had received little recognition. Apparently it was this fibrosing process
evident within 2 glands that led Ewing47 to his original assumption of identity
of the 2 types of thyroiditis.
The relationship of Riedel's struma to subacute thyroiditis has been a more
recent consideration. De Quervain and Giordanengo40 state that the gland in
subacute thyroiditis may simulate struma fibrosa (Riedel) in hardness, but
establishment of the identity of the 2 diseases is not possible at present. Schilling125 regards them as different manifestations of thyroid response to inflammation. Crile 24,28 considers them separate diseases. Certainly the complete preservation of the thyroid capsule in subacute thyroiditis leads to no possibility of
error in morphologic interpretation. Common to both diseases is the complete
or nearly complete destruction of thyroid tissue over broad areas, without
respect for lobular architecture, fibroplasia and the elements of inflammation.
The following are distinguishing characteristics of Riedel's thyroiditis, as compared with subacute thyroiditis: (a) history of previous goiter; (b) absence of
pain in the thyroid gland or throat; (c) fibroblastic invasion of thyroid capsule
and adjoining cervical structures and (d) an insignificant or absent granulomatous
lesion. So far as can be determined from the literature, there is no recorded
instance in which a transition from one to the other disease has occurred. Crile28
states that he has noted no such transformation among any of 100 cases of
subacute thyroiditis. Even though an etiologic relationship with subacute
thyroiditis cannot be disproved entirely, the evidence at present necessitates
distinction of the two diseases as entities both clinically and pathologically.
April 1955
THYROIDITIS
417
Clinical Features
The characteristic clinical manifestations are the complaint of severe pressure
symptoms, in the presence of a goiter that may not be unduly large, but always
is of distinctly stony-hard consistence and densely fixed to cervical structures.77
Often there is a history of previous goiter of several months' or years' duration,
which suddenly77 •80 •88 or slowly24'94 has enlarged. Crile24 found an average
duration of 29 months before operation. The pressure symptoms predominate
and are out of proportion to the size of the mass. 77 ' 88 They appear early, often
are intense because of extensive tracheal involvement,88 and consist of suffocating
attacks, stridulous cough and dyspnea.77 Riedel stated that the broadened
isthmus may prevent tracheotomy, and Joll77 agrees that this operative procedure may not give relief. There have been several cases of unilateral laryngeal
paralysis. 24,77
The goiter may be small but always is firmly fixed and intensely hard, exceeding the consistency even of carcinoma.24' "• U8 ' 125 The enlargement is unilateral
in about one third to one half the cases. 24 ' 46 ' Mi 5S The regional lymph nodes are
not enlarged, 46,68 or rarely so.54
As a rule, there are no local symptoms of pain,87 tenderness or referred pain,46 •77
though these may occur.24 Systemically, there are few complaints.24 There usually
is no fever.24'88 Generally, the thyroid function is normal, although with bilateral
involvement there may be hypothyroidism and very rarely myxedema. 77 ' 8S
The principal clinical differential diagnosis is malignant disease of the thyroid
gland. Malignant disease can be disproved or confirmed only by operation and
adequate biopsy. Of the rarely occurring diseases of the thyroid gland, syphilis,
and tuberculosis and actinomycosis are to be considered.46' M
Clinical Laboratory Findings
The routine laboratory findings are not remarkable; there may be a mild
leukocytosis.54 Crile24 found the blood sedimentation rate elevated moderately
in one case. The basal metabolic rates usually are within normal limits except
in extensive bilateral involvement, when they are low. Crile24 records an average
of plus 2 per cent, but in a case where there was destruction of both lobes, it was
minus 20 per cent. McConahey and Keating" found a range of minus 23 to plus
13, and a mean of minus 4.4 ± 6.2. The I131 uptake is in the normal range.99, 144
Pathologic Anatomy
The lesion is characterized by extension beyond the thyroid capsule, so that
not only the thyroid gland but the entire anterior cervical region—carotid
sheath, trachea, muscles—is involved in a diffuse fibrosis.26, 64' f&' 69 At operation,
complete removal of a thyroid lobe is impossible because of the entire loss of
thyroid capsule, and the invasion of muscle, nerves and blood vessels by the
inflammatory mass. In no area is the surgeon able to find dissectable tissue
planes, and bleeding usually is profuse. The goiters may be bulky or small. 24 ' 44 ' 77
Regardless of size, the infiltrative lesion constricts and flattens the trachea,58 so
that it becomes slitlike and reduced in caliber for a variable and often considerable extent.
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HAZARD
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The tissue on section is gritty, white without any resemblance to thyroid
tissue and is of a hardness and density that blunt the knife.77 The cut surface is
dull white or yellow white. The tissue is fibrous, and may be concentrically
layered.94 There is no pseudolobulation, and in the available specimen there is no
evident normal thyroid tissue or at most only a few colloid-containing areas.77
The dense white mass incorporates the thyroid gland and the cervical soft tissues
into an inseparable mass.
Because of the invasive feature the surgical specimens bear no resemblance to
a thyroid lobe, consisting of blood-stained, tough, white, fibrous tissue and tags
of muscle.
An adenoma may.be present in the goiter 24 ' 62 ' 94 ' 125 and is recorded in two
thirds of Crile's cases24 and in both of those of Lindsay and his associates.94 In
such a circumstance, incision of the involved lobe at operation and removal of
the anterior segment of dense fibrous tissue expose the adenoma, which may be
enucleated as a unit or, otherwise removed.
The major portion of the lesion is formed by fibrous tissue of adult type, and
there is complete obliteration of any previous lobular structure of the gland. The
follicles mostly are absent and when found are shrunken, round, formed by small
atrophic epithelial cells and may contain colloid. These are surrounded by, and
isolated in, fibrous tissue that may be fibroblastic or collagenous, but often is
hyaline. Oxyphilic epithelial cells of Hiirthle type never are found. An exudate
of variable degree is present consisting of lymphocytes, plasma cells, neutrophils
and occasionally eosinophils.68 The lymphoid infiltrate never is prominent and
is not diffuse.77 The leukocytes may form microabscesses. Although giant cells
may occur, they always are scarce,24' 126 and in no instance is the change pseudotuberculous.
The connective tissue, especially peripherally, may be fibroblastic,77 and it
infiltrates the perithyroid musculature, extending between and isolating individual muscle fibers.
When an adenoma is present, it is of follicular type, and may show the cystic
and calcific changes common in such lesions. The capsule is thickened by fibrous
tissue and contains a mild inflammatory infiltrate similar to that found in the
surrounding tissue. Despite the fact that the capsule of the adenoma resembles
that of the fibrotic tissue replacing the gland itself, outer margination is reasonably sharp.
Because of the operative difficulties, identifiable thyroid tissue seldom is
obtained. .Toll77 describes well-formed follicles outside the areas of major involvement.
There are several features of differential diagnosis worthy of comment. Though
the lesion is characterized by its extension beyond the thyroid capsule, the
histopathologic changes within the gland are nonspecific and similar to those
that may be found in subacute thyroiditis. However, the absence of a pseudotuberculous pattern distinguishes the process from the latter. The fibroblastic
infiltration of muscle may suggest fibrosarcoma or spindle-cell carcinoma when
only small biopsies are available, but the excellent differentiation of the fibro-
April 1955
THYKOIDITIS
419
blasts and the accompanying inflammation in Riedel's struma are distinguishing
features. There should be no confusion with the fibrous variant of struma lymphomatosa; the distinctive major comparative features of Riedel's thyroiditis are
the loss of thyroid capsule, loss of lobular architecture, absence of oxyphilic
cells and absence of diffuse lymphoid infiltration.
Treatment
Treatment is directed toward the relief of pressure either by direct decompression of the trachea or by halting the progress of the inflammatory mass. Because
of the infiltrative character of the lesion, the surgical excision of much of the
goiter is difficult and hazardous.68 .Toll77 does not consider removal of a wedge of
tissue as sufficient for relief; Goodman58 regards radical surgery as unnecessary
and dangerous and recommends a wedge resection over the trachea. Crile24
suggests splitting the enlarged lobe to locate an adenoma, removing a cap of
tissue and enucleating the central nodule. Roentgen therapy is regarded as
being ineffective.24 Crile24 reports progress of the disease; in one case, to hypothyroidism, parathyroid involvement and tetany, despite radiation.
Course
The lesion itself is considered benign, but death may occur because of the
severe and extensive tracheal compression. The disease has been regarded as
self-limited;44 however, the progress of the inflammation may be arrested by
removal of an adenoma,24 or even a small portion of the goiter.44' 58 Goodman68
states that all induration of the neck may disappear within a few months.
Others 24,72, "° have noted that the tumor may recur on the resected side and
also may appear in the other lobe.
There is a paucity of adequately traced, authentic cases, so that significant
data regarding mortality and ultimate prognosis are not now available. Among
the 41 cases that Graham 59 accepted as Riedel's struma, there were 4 deaths in
the hospital and 2 occurring later. Eisen46 reports the mortality to be 6 per cent
and found that 16 per cent of the patients had a recurrence of their disease. He
states that practically the same results were obtained regardless of the surgical
procedure or the amount of tissue excised.
D. Lymphocytic Thyroiditis (Lymphoid Thyroiditis)
Lymphocytic thyroiditis is characterized by the rapid diffuse enlargement of
a previously normal gland and usually occurs in a young woman, an adolescent,
or a child.28, 66 Generally there is no clinical evidence of hypothyroidism.28
For some years certain sporadic cases of goiter in young people and children,
have been regarded as struma lymphomatosa occurring at an early age. Schilling125 urged careful evaluation of such cases. Graham, 61 in discussing a paper by
Lehman and Maiden, refers to a boy 9 years of age with hypothyroidism and a
goiter with much lymphoid tissue but without the type of epithelium found in
Hashimoto's struma. This latter histopathologic feature is an important distinguishing characteristic.
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25
Incidence
The general prevalence is unknown. Gribetz and his associates65 state that the
disease comprises about one third of the cases of nontoxic goiter seen at the
Adolescent Endocrine Clinic at the Massachusetts General Hospital, and record
the lesions in 6 of 8 girls on whom biopsies were performed. In their series the
age range was 9 to 13 years; Crile26 has observed the disease in young women.
Lymphocytic thyroiditis occurs predominantly in females.
Etiology and Pathogenesis
Gribetz and his co-workers65 found elevated concentrations of serum proteinbound iodine (PBI) with a low butanol-extractable fraction (BEI) in the serums
of patients with lymphocytic thyroiditis. Basing their opinion on this finding,
they suggest that the changes in the thyroid gland are compensatory and a
manifestation of a disordered synthesis and release of thyroid hormone. With an
abnormal and hormonally ineffective secretory product, there is no inhibition of
thyrotrophic-hormone formation by the pituitary gland; this causes an increased
thyroidal secretion that continues until the blood levels of effective thyroid
hormone become normal. Support is given to this theory by the fact that administration of desiccated thyroid causes a disappearance of goiter, and a rise
in the butanol-extractable fraction of protein-bound iodine in the serum.
The histopathologic features suggest that the disease may be an early phase
of struma lymphomatosa. Graham62 considers it a form of lymphadenoid goiter;
Gribetz and his co-workers65 regard it parenthetically as Hashimoto's disease.
So far, however, there appears to be no proof that a direct relationship exists.
The levels of serum PBI usually found are not those found in struma lymphomatosa. At present it is not possible to deny or to accept a relation between
these two diseases, but there is sufficient evidence to consider them distinct
clinicopathologic entities.
Clinical Features
The main complaint is the appearance of goiter. Crile26 states that enlargement of the thyroid gland frequently is noted following childbirth. The disease
occurs predominantly in females, commonly in the age group of 20 to 40 years
and in children.65 Clinical evidence of mild hypothyroidism may occur;25 in 1
case, Gribetz and his co-workers65 noted retardation in skeletal maturation
suggestive of a hypothyroid state. The thyroid gland is enlarged 2 to 4 times
normal size, is firm and retains its outlines; Gribetz and his co-workers65 record
a coarsely granular character to the gland on palpation. In one half of the cases
reported by these authors, the goiter was nodular and, in a like number, the
pyramidal lobe was palpable. They also found that the Delphian lymph nodes
were enlarged in 3 of their 6 cases. There may be mild pressure symptoms. 25 The
signs and symptoms of thyrotoxicosis are absent.
Of clinical importance in differential diagnosis are carcinoma, subacute
thyroiditis and goiter caused by iodine deficiency. Biopsy is essential for accurate diagnosis. Crile25 has found needle biopsy successful, and Gribetz and
his co-workers65 made the diagnosis in 2 of their cases by this method.
April 1955
THYROIDITIS
421
Clinical Laboratory Findings
The routine laboratory tests are negative, the basal metabolic rate is usually
below zero.28 Most important are the changes, recorded by Gribetz and his
associates:66 values for the serum protein-bound iodine were elevated in 3 cases,
low and normal in 2. The butanol-extractable iodine fraction was in the lownormal range in the 2 patients studied, each of whom had elevated values for
protein-bound iodine. The radioiodine uptake showed no significant change,
values being low normal to high, with a range of 25 to 84 per cent accumulation
in 48 hours.
Pathologic Anatomy
Grossly, there usually is diffuse enlargement of the thyroid gland. The capsule
is intact and the contours may be smooth, irregular or nodular.65 On section, the
tissue is gray-white, tan or yellowish-white.65
Microscopically, there is an extensive lymphocytic infiltration with or without
well-formed germinal centers. The epithelium characteristically is without
oxyphilic change; where the latter occurs, it never is diffuse but is in insignificant
foci. The follicles usually are medium or small in size, but they may be large.
The epithelium is cuboidal or low columnar and the layer of follicular cells in
many glands reveals infoldings such as those seen in functional hyperplasia.62, 65
The colloid usually is reduced in amount and is granular; in some follicles it is
absent. Macrophages frequently are present in the acinar lumens; there is no
tubercle formation. Fibrosis is variable both in amount and in distribution.
The lesion differs from that of struma lymphomatosa by an absence of oxyphilic
epithelium or its presence only in small foci. Subacute thyroiditis is not of
diagnostic importance, differentially, since there is no focal granulomatous
reaction in lymphocytic thyroiditis. The follicular changes may be difficult to
distinguish from those found in the gland of hyperthyroidism. The differential
features appear to be the absence or granular state of the colloid and the frequent intrafollicular macrophages. A clinicopathologic correlation permits the
most accurate establishment of diagnosis. The feature of hyperplasia may
suggest carcinoma, but the orderly architecture of parenchyma and stroma,
well-preserved lobulation and well-differentiated follicles are differential points.
Although extensive lymphocytic infiltration has been described in conjunction
with papillary carcinoma,27 it is rare, and in these reported cases histopathologically was distinct and obvious.
Treatment
The immediate response to the administration of desiccated thyroid is dramatic
in most cases, but the goiter may recur if the treatment is stopped. 25,26, 86
Gribetz and his co-workers65 found that the values for serum protein-bound
iodine fell and that those for the butanol-extractable fraction rose after therapy
so that a normal PBI-BEI relation resulted. They also noted that the fall in
PBI may not be accompanied by a reduction in the size of the enlarged thyroid
gland. Radiation may give relief from goiter but usually neither this treatment
nor surgical therapy is needed.26
422
HAZARD
Vol. 25
E. Sarcoidosis
Though sarcoidosis may occur in any part of the body, the thyroid gland
rarely has been reported as a site of the disease. So far as can be determined, it
never has appeared as a primary lesion of the gland. Spencer and Warren133 report a case of thyroid involvement as a part of generalized sarcoidosis. Recently,
Cummins, Clark and Gandy31 described the disease in a specimen of thyroid
gland from a patient with exophthalmic goiter. The lesions appear as gray-white,
circumscribed nodules, less than 0.5 cm. in diameter, scattered in variable
number throughout the gland. Histopathologically, the lesions are similar to
those of sarcoidosis elsewhere. However, Cummins and his associates31 found a
rather marked lymphocytic infiltration in the vicinity of the tubercles in the
gland of hyperthyroidism.
F. Chronic Thyroiditis of Unclassified Type
Regardless of any attempt to provide a complete classification of the diseases
of an organ, there always remain certain lesions with morphologic features
that are not sufficiently specific for definite designation. Respecting the thyroid
gland, within the scope of this review these may be grouped as unclassified
thyroiditis. The general manifestations are fibrosis and lymphoid infiltration,
without specific change regarding the type of epithelium or the pattern of
reaction. Because of the nonspecific character of the lesions, a detailed description of the pathologic changes is unwarranted.
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