Anaplastic Thyroid Carcinoma

A Study of 70 Cases

MARIA LUISA CARCANGIU, M.D., THERESA STEEPER, M.D., GIANCARLO ZAMPI, M.D.,
AND JUAN ROSAI, M.D.

Seventy cases of anaplastic thyroid carcinomas studied at the Institute of Pathologic Anatomy, University of Florence
Universities of Florence (Italy) and Minnesota are presented. Medical School, Florence, Italy, and the Division of Surgical
Three morphologic patterns were seen: spindle, giant cell, and Pathology, Department of Laboratory Medicine and
squamoid, sometimes in combination. Ultrastructurally, evidence Pathology, University of Minnesota Medical School,
of epithelial differentiation was seen in most but not all cases Minneapolis, Minnesota
studied. Immunohistochemically, a stain for cytokeratin using
a monoclonal antibody was found the most useful adjunct to
diagnosis. Unexpected positivity for carcinoembryonic antigen
(CEA) was found in several squamoid tumors. The alleged

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frequent positivity of this tumor type for thyroglobulin and Material and Methods
calcitonin was not confirmed. A third of the tumors were
associated with a better differentiated component, of which, The cases presented in this article were obtained by
presumably, they represented a dedifferentiation. The extremely searching the files of the Departments of Pathology of
aggressive behavior of anaplastic thyroid carcinomas was con- the University of Florence, Italy, and the University of
firmed amply in this series: all of the patients in whom follow-
Minnesota, Minneapolis, Minnesota. Thyroid tumors
up information was available died of their tumor. Small cell
tumors should not be included into the anaplastic category, coded under the diagnoses of anaplastic carcinoma,
since they invariably belong to other groups, i.e., malignant undifferentiated carcinoma, malignant lymphoma, sar-
lymphoma, medullary carcinoma, and poorly differentiated coma, small cell tumor, and unclassified malignant
("insular") carcinoma. (Key words: Thyroid gland; Thyroid tumors were reviewed. Twenty-two cases were eliminated
neoplasms; Anaplastic carcinoma) Am J Clin Pathol 1985; 83:
because, on review, they were thought not to fulfill the
135-158
criteria for this entity. Seventy cases were accepted to
have the features of anaplastic thyroid carcinoma: 39
ANAPLASTIC (undifferentiated, sarcomatoid, dediffer-
were from Florence, Italy; 18 from the University of
entiated) thyroid carcinoma is one of the most aggressive
Minnesota Hospitals, Minneapolis, Minnesota; and 13
malignant tumors in the human body. Although it has
had been sent in consultation to one of us (J.R.). This
been well recognized for many years as a distinctive
material represents 6.5% and 4.9% of all primary thyroid
clinicopathologic entity, some changing views have de-
malignancies seen at these two institutions, respectively.
veloped in recent years in this field. They include the
The clinical charts were reviewed in all cases. Follow-
realization that thyroid tumors composed of small cells
up information was obtained in 57 cases.
do not belong into this category,5 and the claim that a
Hematoxylin and eosin-stained slides were available
high proportion of anaplastic thyroid carcinomas have
in all cases. In addition, slides from 48 cases were
staining qualities that link them with medullary carci-
stained with Grimelius27 and Churukian15 technics for
noma.55 A continuing source of controversy regards the
argyrophil granules and with Sternberger's immunoper-
frequency and very existence of true sarcoma of the
oxidase technic73 for calcitonin, diluted 1:150 (Immuno
thyroid gland, particularly angiosarcoma.
Nuclear Corp.); carcinoembryonic antigen (CEA), diluted
It is the purpose of this article to review the clinical
1:800 (Accurate Chemical & Scientific Co.); thyroglob-
and pathologic findings in 70 cases of anaplastic thyroid
ulin, diluted 1:3,200 (Cal Med); epidermal-type keratin,
carcinomas studied in two institutions and to compare
diluted 1:160 (Accurate Chemical & Scientific Co.); and
findings with those of the previous literature on the
cytokeratin, diluted 1:4,000 (Enzo Biochem). The epi-
subject.
dermal-type keratin had been isolated from human
calluses, and the antibody against it was of polyclonal
Received May 1, 1984; received revised manuscript and accepted type, raised in rabbits. The cytokeratin preparation, with
for publication July 6, 1984.
Address reprint requests to Dr. Rosai: Box 76 Mayo Memorial a M.W. of 54 kdalton, had been isolated from human
Bldg., University of Minnesota Hospitals, Minneapolis, MN 55455. hepatoma cells, and the antibody used was monoclonal.26

135
136 CARCANGIU
The sections used for these stains were obtained from
material that had been fixed in 10% neutral buffered
formalin or 95% ethanol and embedded in paraffin.
Seven of the cases also were studied ultrastructurally.
Tissue was fixed in 2.5% buffered glutaraldehyde, post-
fixed in osmium tetroxide, and embedded in Epon; the
sections were stained sequentially with uranyl acetate
and lead citrate and examined with a Philips® 201
electron microscope.
Description of Cases
Clinical Features
The total number of cases included in the study was
70. There were 17 male patients and 53 female patients,
resulting in a male:female ratio of 1:3.1. The age at the
time of initial diagnosis ranged from 37 years to 90
years, with a mean of 66.5 years. All but three of the
patients were older than aged 50 years at the time of
diagnosis. None of the patients gave a history of radiation
exposure to the thyroid region during childhood or
adolescence. All patients were euthyroid at the time of
the diagnosis; one patient had a history of hyperthyroid-
ism treated medically three years previously. A preceding
history of long-standing nodular or diffuse goiter was
obtained in 12 (30.8%) of the cases from Italy but in
only one (3.2%) of those from Minnesota. Three patients
had had previous surgery to the thyroid gland for the
following reasons: "adenoma"—one case (slides not
available), papillary carcinoma—two cases.
All patients presented with a rapidly enlarging firm
to hard neck mass, which, in at least half of the cases,
was associated with one or more of the following symp-
toms: dysphonia (hoarseness), dysphagia, and dyspnea
(colloquially known as the three Ds). Characteristically,
the duration of these symptoms was very short, ranging
from two weeks to ten months. On physical examination,
the tumor was felt to extend beyond the thyroid gland
in about half of the cases and was associated with
enlargement of cervical nodes in 20. As a group, the
cases from Florence were more advanced at the time of
initial presentation than those from Minnesota. Distant
metastases were recorded at the time of presentation in
11 patients. They were located in the following sites:
lung, ten; bone, two; stomach, one; skin of back, one.
Forty-two tumors were considered unresectable at the
time of presentation, and only palliative surgical proce-
dures were performed; these included decompression,
tracheostomy, sternotomy, and gastrostomy. This was
combined with a biopsy of the tumor or, at the most,
the removal of a portion of a lobe. In 28 cases, an
operation with curative intent was carried out. This
consisted of a lobectomy in nine cases, subtotal thyroid-
ectomy in four, and total thyroidectomy in 15. A radical
ET AL. A.J.C.P.. February 1985
neck dissection was performed in nine instances. The
most extensive operation in the series consisted of an
en bloc resection of the entire thyroid gland, bilateral
neck dissection, and the removal of the trachea and
esophagus directly involved by tumor.
Seventeen patients received postoperative external
radiation therapy (2,335 to 5,950 rads), and 13 were
administered various chemotherapeutic drugs, including
adriamycin, nitrogen mustard, 5-fluorouracyl, Cytoxan,
bleomycin, and vincristine, singly or in combination.
The evolution of this tumor following initial therapy
was remarkably rapid and usually characterized by
extensive growth in the neck, with involvement of
carotid vessels, larynx, trachea and/or esophagus. In
addition to the 11 patients who had evidence of disease
outside the neck at the time of presentation, 14 more
developed distant metastases, for a total incidence of
35.7%.
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Of the 57 patients with follow-up information, all
died of tumor; 12 did so in the immediate postoperative
period, 35 additional patients within six months, and
the other 10 patients within 2.5 years. It was felt that
the immediate cause of death was massive local growth
with involvement of vital structures in 44 cases, wide-
spread distant metastases in 7, and the combined effect
of local and distant disease in 6. The mean duration of
survival from the time of tissue diagnosis was four
months. A complete autopsy was carried out in nine
cases. This showed extensive local growth with invasion
of neighboring structures and regional nodes in all nine,
associated with distant metastases in seven. These were
located in adrenal (five), lung (three), heart (two), kidney
(one), brain (two), spleen (one), and bone (one).
No differences were found between the evolution of
the disease (as measured by the mean survival time)
and the following parameters: age; sex; microscopic
pattern; and presence or absence of extrathyroid spread,
or of a well-differentiated component.
Gross Appearance
In most cases, only small fragments of granular,
friable, whitish or grayish tissue were received. The
larger specimens showed a tumor mass extensively infil-
trating the thyroid gland, often containing foci of necrosis
and hemorrhage. Remnants of a capsule were described
in five cases. Two tumors were predominantly cystic,
with mural nodules protruding into the lumen. Extra-
thyroid extension often was noted. The largest tumor
weighed 300 g and measured 12 X 7.5 X 6.3 cm.
Light Microscopic Appearance
Three rather distinct morphologic patterns were iden-
tified, allowing for the fact that transitions and inter-
mediate forms often occurred among them. These pat-
Vol. 83 • No. 2 ANAPLASTIC THYROID CARCINOMA
terns were descriptively designated as spindle, giant cell,
and squamoid.
A spindle cell component was seen, singly or in
combination, in 37 (52.8%) of the cases. Its appearance
could be described best as sarcomalike and was indeed
indistinguishable from a true sarcoma in most areas.
The nuclei were hyperchromatic, and mitotic figures
(some of them atypical) were numerous. Some foci
closely resembled the appearance of fibrosarcoma by
virtue of their fascicular arrangement and a heavy
deposition of reticulin and collagen fibers.21 In most
places, however, the marked degree of nuclear pleomor-
phism, and the appearance of scattered giant tumor
cells, storiform pattern of growth, and an inflammatory
infiltrate gave the tumor an appearance highly reminis-
cent of that exhibited by the usual type (storiform-
pleomorphic) of malignant fibrous histiocytoma21 (Fig.
1). These cellular foci alternated with extensive areas of
necrosis and large expanses of sclerohyaline tissue. The
necrotic foci often had sharply angulated outlines and
were surrounded by a palisading of tumor cells, the
resulting image being reminiscent of that seen in malig-
nant glial tumors of the central nervous system (Fig. 2).
Areas of extensive myxoid change often were seen
(Fig. 3).
In general, these tumors were well vascularized. In
several instances, the prominent branching vessels with
"staghom" or "antler-like" appearance closely simulated
the architectural pattern of hemangiopericytoma21 (Fig.
4). Other foci resembled the appearance of angiosarcoma
through the formation of anastomosing channels lined
by tumor cells (Fig. 5). A highly characteristic formation
seen in the spindle cell areas resulted from the permeation
of the wall of large-sized veins (Fig. 6A) and arteries
(Fig. 62?) by neoplastic cells. Sometimes, these vascular
formations stood out in a sea of necrotic or hyalinized
tissue (Fig. 6C).
The giant cell pattern was present in 35 (50%) of the
cases. It was characterized by a striking degree of pleo-
morphism (more so than in the spindle areas) and the
presence of numerous tumor giant cells, having bizarre,
sometimes multiple hyperchromatic nuclei, abundant
acidophilic cytoplasm, and a plump, oval or round
shape (Fig. 7). Some of these cells had their cytoplasm
crowded with large hyaline globules. These giant cells
were interspersed among smaller mononuclear tumor
cells having similar cytoplasmic features. The pattern of
growth was usually solid, but sometimes an artifactual
separation of the cells led to the formation of alveolar,
pseudoglandular or pseudovascular structures (Fig. 8).
The latter were particularly prominent in the areas
where the highly vascular nature of the tumor had led
to the accumulation of numerous red blood cells within
these cavities. A diagnosis of angiosarcoma initially had
been considered in several of these cases, but the overall
137
microscopic appearance and the negativity for Factor
VIH-related antigen were against this possibility.
An inflammatory component was usually present
among the tumor cells; this was sometimes heavy and
predominantly neutrophilic in type, giving the tumor
an appearance closely resembling that of the so-called
inflammatory variant of malignant fibrous histiocytoma21
(Fig. 9). Sometimes, the giant tumor cells contained
numerous neutrophils in their cytoplasm (Fig. 9, inset),
as described in the latter tumor and also in giant cell
carcinomas of other organs, such as lung and adrenal
cortex.35
In the more solid portions, the polygonal shape of
the cells and their well-defined borders resulted in an
epithelial-like appearance, which was enhanced here and
there by the formation of tumor nests exhibiting periph-
eral palisading. In these areas, the cytoplasm of the
tumor cells was sometimes clear, or deeply acidophilic
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and granular. Although the alternative diagnoses of clear
cell carcinoma and Hurthle cell carcinoma could have
been considered for these two patterns, respectively, we
chose to include these tumors into the anaplastic category
if all the other features (such as pleomorphism, high
mitotic activity, and necrosis) were present.
The third pattern, seen in 13 (18.6%) cases, was
designated as squamoid, by virtue of its morphologic
similarity with nonkeratinizing and (less commonly)
keratinizing squamous cell carcinoma. The appearance
in these areas was unmistakably epithelial (Fig. 10).
Tumor nests and islands of irregular configuration were
prominent. Pleomorphism was mild to moderate, and
giant cells generally were absent. The cytoplasm was
abundant and had acidophilic staining qualities. Rarely,
squamous pearls were seen in the center of the islands.
In a single case, pools of mucin were seen among the
squamoid elements and in the cytoplasm of some tumor
cells.
None of the tumors exhibited areas of clear-cut car-
tilaginous or osseous differentiation. Features common
to all three patterns were high mitotic activity, large foci
of necrosis, and a marked degree of invasiveness, both
within the gland and in the extrathyroid structures.
Actually, many of the specimens consisted only of a
small biopsy taken from the extrathyroid extension of
the tumor. Malignant cells were seen to insinuate them-
selves between residual follicles and to invade fat and
skeletal muscle and sometimes even ulcerate through
the skin (Fig. 11). On occasion, the neoplastic cells
penetrated within the skeletal muscle fibers, in a fashion
akin to that seen in carcinomas of breast and other
organs70 (Fig. 11, inset). Blood vessel invasion, in the
form of tumor emboli (and distinct from the wall
permeation described in the spindle cell areas) frequently
was encountered in all three patterns.
Multinucleated cells of osteoclast-like appearance were
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FlG. 1 {upper). Spindle cell growth with storiform pattern, simulating malignant fibrous histiocytoma. Hematoxylin and eosin (X200).

FIG. 2 {lower). Sharply outlined area of necrosis surrounded by a palisading of tumor cells,
similar to that commonly seen in malignant glial tumors. Hematoxylin and eosin (X200).
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FIG. 3 (upper). A highly myxoid background separates the tumor cells, as in the myxoid variant
of malignant fibrous histiocytoma. Hematoxylin and eosin (X200).
FIG. 4 (lower). Numerous branching vessels with a "staghorn" configuration,
reminiscent of hemangiopericytoma. Hematoxylin and eosin (X200).
140 CARCANGIU ET AL. A.J.C.P. • February 1985

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FIG. 5. Anastomosing channels and papillary fronds are reminiscent of angiosarcoma. Immunocytochemical
stain for Factor Vlll-related antigen was negative. Hematoxylin and eosin (X200).

found among the neoplastic elements in eight cases,
sometimes in abundance (Fig. 12). They had numerous
small nuclei, devoid of atypical features, and never were
seen undergoing mitotic division. These eight tumors
were all of spindle and/or giant cell type rather than
squamoid. In three of the cases, the stroma had a
myxochondroid aura, but without featuring well-devel-
oped tumor cartilage or bone.
As already mentioned, transitions and admixtures
between the three major patterns often were seen. The
more common were between the spindle cell and pleo-
morphic areas (Fig. 13), but sometimes foci with an
appearance indistinguishable from a sarcoma merged
with others having a clear-cut epithelial configuration.
Residual foci of papillary carcinoma were found in
14 cases. Papillae and follicles lined by cells with ground
glass nuclei were seen surrounded by the undifferentiated
component, which, on occasions, also permeated the
stroma of the papillae. Interestingly, some of the nuclei
in the squamoid tumors associated with papillary car-
cinoma were large and clear, resembling the "ground
glass" nuclei seen in the papillary areas. In eight cases
remnants of a well-differentiated follicular nodule were
identified. In three, there were enough architectural
features to allow the diagnosis of follicular carcinoma;
in the other five no decision could be reached whether
the follicular nodule was a carcinoma, an adenoma, or
an adenomatoid nodule, because of the scarcity of this
component. In one case, a residual focus of Hiirthle cell
carcinoma was present, having follicular and solid pat-
terns of growth. Finally, three cases had the features of
the tumor that we have designated as poorly differentiated
(insular) carcinoma13 (Fig. 14). In several cases, well-
circumscribed, totally hyalinized (sometimes also calcified
and ossified) round nodules were seen surrounded by
the anaplastic component; in some of them, well-differ-
entiated follicular structures were noted, suggesting that
they represented follicular nodules with extensive re-
gressive changes. This phenomenon may be analogous
to that sometimes seen in ancient mixed tumors of
salivary glands that have undergone malignant transfor-
mation. The total incidence of residual better differen-
tiated tumor that could be identified confidently as
malignant was 30% for the whole series and 15% for the
subset of cases from Florence.
In all but one of the cases associated with a well-
Vol. 83 • No. 2 ANAPLASTIC THYROID CARCINOMA 141

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FIG. 6. Permeation of medium-sized vessels by
tumor. A (upper, left). Polypoid projection in the
lumen of a vein. Hematoxylin and eosin (X200). B
(upper, right). Replacement of the subendothelial
region in an artery. Hematoxylin and eosin (X200).
C (lower). Occluded vessel surrounded by hyalinized
tissue. Hematoxylin and eosin (X200).
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FIG. 7 (upper). Giant cell pattern. The cytoplasm is abundant and highly eosinophilic;
the nucleus often is pushed toward the periphery. Hematoxylin and eosin (X50Q).
FIG. 8 (lower). Alveolar pattern resulting from lack of cohesiveness of the tumor cells. Hematoxylin and eosin (X200).
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FIG. 9 (upper). A heavy neutrophilic infiltrate present between the tumor cells simulates the appearance of the inflammatory variant of
malignant fibrous histiocytoma. Hematoxylin and eosin (X500). Inset. Numerous neutrophils present in the cytoplasm of a tumor giant cell.
Hematoxylin and eosin (X500).
FIG. 10 (lower). Squamoid tumor nests are separated by a desmoplastic stroma. Hematoxylin and eosin (X200).
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FIG. 11 (upper). Tumor growth between skeletal muscle fibers. Hematoxylin and eosin (X200).
Insel. Penetration of tumor cells within skeletal muscle fibers. Hematoxylin and eosin (X500).
FIG. 12 (lower). Numerous osteoclast-like giant cells are seen in a tumor with a myxoid background. Hematoxylin and eosin (X200).
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FIG. 13 (upper). Admixture of giant cell and spindle cell patterns in the same neoplasm. Hematoxylin and eosin (X500).

FIG. 14 (lower). Anaplastic spindle cell carcinoma growing between the "insulae"
of a poorly differentiated carcinoma. Hematoxylin and eosin (X200).
146 CARCANGIU ET AL.
differentiated tumor, the anaplastic component consti-
tuted the bulk of the mass. The only exception was a
case of follicular carcinoma with a small nodule of
anaplastic cells outside the capsule.
The microscopic appearance of the metastases recapit-
ulated in every respect those of the primary neoplasms.
In those tumors which had a residual better differentiated
A.J.C.P. • February 1985
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FIG. 15. A (upper, left). Coarse argyrophilic granules occupying
part of the cytoplasm in several tumor cells (Churukian's technic)
(X800). B (upper, right). A finer and more diffuse pattern of
cytoplasmic argyrophilia is seen in the necrotic portion of the same
tumor (Churukian's technic) (X800). C (center, left). Foci of strong
CEA positivity are present in a tumor with squamoid pattern.
(X500). D (center, right). An entrapped nonneoplastic follicle shows
strong cytoplasmic and intraluminal positivity for thyroglobulin,
but the tumor cells are negative. The isolated positive cell seen in
the right lower corner of the photograph also is regarded as
nonneoplastic (X500). E (lower). Entrapped follicles show marked
positivity for cytokeratin; some of them are solid and distorted and
could be easily misinterpreted as neoplastic (X200).
component, only the anaplastic portion was represented
in the distant foci.
Histochemical and Immunohistochemical Features
Argyrophil stains with the Grimelius' and Churukian's
technics were comparable. They showed positive tumor
Vol. 83 • No. 2 ANAPLASTIC THYROID CARCINOMA
I*
r
* ^* *tf
FlG. 16. Strong cytoplasmic positivity for cytokeratin is seen in most tumor cells, regardless of their size and shape (X500).
Inset. A spindle cell of sarcomatoid appearance is also markedly reactive (X800).
cells in 12 cases. The staining was always focal, confined
to a few tumor cells, and appeared in the form of coarse
cytoplasmic granules (Fig. 15A). Curiously, a pattern of
diffuse fine cytoplasmic granularity was seen only in
areas of obvious necrosis (Fig. 155). Coarse granular
positivity also was sometimes seen in the follicular cells
present in the nonneoplastic gland.
Stains for calcitonin showed a coarse focal cytoplasmic
stain in a few tumor cells in four cases. The pattern was
very different from the diffuse, homogeneous staining
seen in the medullary thyroid carcinoma used as control.
Furthermore, preabsorption of the antiserum with a
purified calcitonin preparation did not influence at all
the staining reaction in these cases, whereas it completely
abolished the stain in the medullary carcinoma control.
Stains for CEA showed focal strong positivity in six
cases. These were all of the squamoid pattern, and the
positivity usually was seen in the center of the tumor
nests (Fig. 15C).
Stains for thyroglobulin were always negative in the
tumor cells. In contrast, entrapped nonneoplastic follicles
reacted strongly. Occasional strongly positive isolated
cells were seen only in close proximity to the follicles
and therefore were interpreted as being nonneoplastic
147
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(Fig. 15D). Sometimes, diffusion of thyroglobulin oc-
curred immediately around the entrapped follicles, so
that the neoplastic cells in this area showed spurious
staining. Those tumors associated with a well-differen-
tiated component showed consistently a positive reaction
for thyroglobulin in the latter.
Stains for epidermal-type keratin were positive in 12
cases. In general, the positivity was seen in tumors with
a squamoid pattern of growth or in clearly epithelial
areas present focally in otherwise sarcomatoid neoplasms.
Only in three instances did the giant or spindle cells
show focal positivity for this antigen. Conversely, stains
for cytokeratin often showed an obvious and strong
cytoplasmic positivity. This was apparent in entrapped
nonneoplastic follicles (Fig. 15E) but also in many of
the tumor cells, whether of giant cell, spindle or squamoid
type (Fig. 16). Cytoplasmic positivity for cytokeratin in
the neoplastic cells was seen in 26 (47.2%) of the tumors
in which this stain was performed.
Ultrastructural Appearance
The nuclei of the seven tumors studied ultrastructurally
were large, of somewhat irregular contour, with clumped
148 CARCANGIU ET AL.
chromatin and prominent nucleoli (Fig. 17). In a case
of squamoid carcinoma arising from a papillary carci-
noma, the nuclei in the squamoid area maintained the
finely stippled chromatin pattern seen in the papillary
portions. The cytoplasm, which was generally abundant,
varied in composition from tumor to tumor and even
in different cells of the same neoplasm. In most instances
it had a rather primitive look, being largely occupied by
ribosomes accompanied by scattered mitochondria and
vesicles of endoplasmic reticulum (Fig. 17). Some cells
had a greater concentration of mitochondria (although
never reaching the number seen in the cells of Hiirthle
cell tumors), and others exhibited a prominent devel-
opment of the granular endoplasmic reticulum. Ran-
domly distributed cytoplasmic filaments of the inter-
mediate type (11 nm) were identified in some tumor
cells in three neoplasms. In one case, they were partic-
ularly prominent, forming huge cytoplasmic whorls sur-
rounded by cisternae of endoplasmic reticulum (Fig.
18). In a fourth case, the filaments were of the actin
type (6 nm) and showed focal condensations. In none
of the cases did we see organelles that we could identify
confidently as secretory granules. Membrane-bound,
highly electron-dense cytoplasmic granules were found
in several tumor cells, but their marked irregularity in
size and shape were more consistent with lysosomal
structures. In one case, the cytoplasm of some tumor
cells contained a peculiar structure of unidentified nature
having transverse striations (Fig. 19) with a periodicity
of 8 nm, similar in appearance to structures that have
been seen in bone marrow cells72 and in the tumor cells
of astrocytoma74 and angiosarcoma (personal observa-
tion).
Intercellular junctions were identified in three cases.
Most were of the zonula adherens type, and a few had
short filaments attached to their inner aspect (Figs. 17
and 20). Microvilli of varying length were seen in the
same cases, abutting in irregularly shaped intercellular
spaces (Fig. 20). These were particularly numerous in
the tumors that had an epithelial appearance by light
microscopy, in which often were accompanied by intra-
cellular and extracellular lumina formation (Fig. 21).
Basal lamina material was identified in only one case;
it was present in a discontinuous fashion around only a
few of the cells. Intercellular collagen and amorphous
material were abundant. Other cells present included
neutrophiles, plasma cells, and histiocytes (Fig. 17).
In one case, we had the opportunity to study ultra-
structurally the anaplastic component and also the well-
differentiated tumor that preceded it. The tumor cells
of the latter (a papillary carcinoma with Hiirthle cell
features by light microscopy) had their cytoplasm packed
with mitochondria, numerous basal secretory granules,
and an exuberant microvillous surface (Fig. 22). These
A.J.C.P. • February 1985
features totally were lost in the cells of the anaplastic
tumor (Fig. 23).
Discussion
The findings of this series confirm the strong predi-
lection of this tumor for elderly individuals and their
preference for the female se x. 3 ' 2a3956 - 6166 - 76 ' 77 The
male:female ratio we encountered (1:3.1) was higher
than that of most other reported series, except for that
of Nishiyama and associates56 (1:4.3). The mean age of
our patients at the time of initial tissue diagnosis (66.5
years) was in keeping with that reported in previous
series. Few patients are seen with this tumor below the
age of 50 years. However, exceptions occur: we had a
case in a 37-year-old female patient, Schoumacher and
associates66 reported one in a 30-year-old person, and
Albores-Saavedra and colleagues3 have the youngest
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patient on record, seen at the age of 22 years.
The clinical presentation was quite uniform, very few
cases departing from the classical description of a rapidly
enlarging thyroid mass, often associated with compres-
sion signs. In one of our patients and in one previously
reported case,7 the presence of skin metastases at pre-
sentation led to some diagnostic difficulties, but even
these two patients had a large thyroid mass when first
seen.
The extreme degree of aggressiveness of this neoplasm
also was corroborated amply. We cannot think of any
other human neoplasm that is so consistently and rapidly
fataj. All of the patients who survived the postoperative
period and in whom we have follow-up information
died as a result of their tumor in a matter of weeks or
months, the longest survival time being 2.5 years. Un-
restrained tumor growth in the soft tissues of the neck
with involvement of vital structures was most often the
cause of the demise, but widespread distant metastatic
involvement also accounted for several of the deaths.
Ten series of anaplastic carcinomas were reviewed by
Casterline and colleagues,14 in a search for patients who
had survived for two or more years after initial diagnosis.
Only 14 were found among 420, i.e., 3.3% of the total.
We attempted a similar evaluation, but found it an
exercise in frustration, especially when we reviewed
papers originating from surgical or radiation therapy
departments in which a direct participation by the
pathologist was lacking. Many of these papers include a
substantial number of small cell carcinomas; some still
list medullary carcinomas in this category; a few include
Hiirthle cell carcinomas; and several series do not even
attempt to break them down into categories or define
their microscopic criteria for inclusion. Although indu-
bitable cases of long-term curves of clinically obvious
anaplastic thyroid carcinomas exist, the overwhelming
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FIG. 17 (upper). Two tumor cells surrounded by neutrophils and other inflammatory cells. Their cytoplasm is abundant and contains
well-developed endoplasmic reticulum (X5,075). Inset. Well-developed junction between two tumor cells (XI 5,840).

FIG. 18 (lower). Intermediate filaments crowd the cytoplasm of a tumor giant cell and displace the organelles and nuclei peripherally
(X7.80O). Inset. High-power view of the filaments, which are nonbranching and measure 11 nm in thickness (XI 5,290).
 Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016

FIG. 19 (upper). Peculiar striated cytoplasmic structure found in the cytoplasm

of the tumor cells in a single case. It has a periodicity of 8 nm (X47,520).
I
FIG. 20 (lower). The cell surface of two tumor cells displays well-developed microvilli and specialized junctions (X4,360).
 ~xr~7
"* ~* / r~. O 6
") -OL i>.

• ^ V - ~ V > ••,::

3" - • / ' ^ J ^ ' . N

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r ^9. ^'.:v.:-.;>. >\

i>_' _ i \ ^ ^ _-G."i-_'^.i ^ •_--^_J. _ j u i ) ^" •••• -'

- .V

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s
'•' s ' --'--At

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'.' -*H
FlG. 21 (upper). This neoplastic cell exhibits numerous microvilli in the surface and within
intracellular lumina. The tumor had a squamoid appearance by light microscopy (X7,700).
FIG. 22 (lower). Papillary carcinoma with Hijrthle cell features. A glandular lumen filled with microvilli is formed by the tumor cells. The
cytoplasm is crowded with mitochondria and contains basally located secretory granules (X2,900). Upper inset. High-power view of mitochondria
(X9,720). Lower inset. High-power view of secretory granules (X9,720).
 CARCANGIU ET AL.
152 A.J.C.P. • February 1985

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••"V^ ^ li'ir:^^l;
FIG. 23. Same case as in Figure 22 after undergoing anaplastic transformation. All the differentiated features previous
exhibited have been lost. The large electron-dense cytoplasmic granules probably represent lysosomes (X7.250).

majority of cases so presented in the literature fall into
one of two categories: (1) tumors of one of the micro-
scopic types described in this article that were found as
an incidental, small (often microscopic) focus in an
otherwise well-differentiated neoplasm,5 and (2) tumors
having a microscopic appearance that no longer is
regarded as belonging to the anaplastic category.
Most of our tumors had spread beyond the thyroid
at the time of initial therapy, and the few that were
described as "intracapsular" were still sizeable and often
associated with nodal or distant metastases. As far as
the second category is concerned, it is our impression
that many of the thyroid tumors included in old (and
some recent) series as anaplastic carcinomas do not
belong into this group. Since none of them share the
degree of malignancy of the bonafide entity, and many
are actually curable, it follows that their proper identi-
fication is crucial. They are the following:
(1) Papillary carcinomas having a solid pattern of
growth but maintaining the cytologic features of the
well-differentiated portions: we and others have shown
that this solid component, when thus defined, does not
worsen the prognosis of papillary carcinoma, even when
it constitutes the predominant portion of the neoplasm.12
(2) Medullary (C cell) carcinomas: before their de-
scription as an entity, they often were placed in the
category of solid or undifferentiated carcinomas. This
error still takes place occasionally, especially when the
tumors have a meager or nil amount of amyloid stroma
and/or exhibit unusual morphologic feature.
(3) Malignant lymphomas of either lymphocytic or
large cell ("histiocytic") type, which usually exhibit a
diffuse pattern of growth when involving the thyroid
gland917: Entrapped follicles, surrounded by the neo-
plastic lymphoid cells and with their lumina "packed"
or "stuffed" by these cells may be interpreted mistakenly
as evidence of follicular differentiation (and hence epi-
thelial nature) of the tumor.17
(4) Poorly differentiated ("insular") carcinoma: This
lesion, which we regard as a distinctive microscopic type
of thyroid malignancy,13 has been placed previously in
Vol. 83 • No. 2 ANAPLASTIC THYROID CARCINOMA
other categories, including that of small cell undifferen-
tiated carcinoma.
Once the above listed entities are removed from the
category of undifferentiated carcinoma, it becomes ob-
vious that the variant of this tumor known as "small
cell carcinoma" is vanishingly rare. This variant has
been subdivided into a "diffuse" and a "compact"
subtype51 by some authors. It is our impression and
that of others that the overwhelming majority of the
tumors formerly diagnosed as the diffuse subtype of
small cell undifferentiated carcinomas50 are malignant
lymphomas5,62,78 and that nearly all those regarded as
the compact subtype of the same tumor are, in reality,
either medullary carcinomas or poorly differentiated
("insular") carcinomas.13,48,52 This has been our experi-
ence, without exception, when reviewing the cases orig-
inally diagnosed as small cell undifferentiated carcinoma
from the files of our respective Universities or sent to
us in consultation with that diagnosis. Heimann and
colleagues33 and Burke and colleagues9 relate similar
experiences from their own Institutions. The differential
diagnostic features between these entities are discussed
in detail in several recent articles on the subject.9,13
All of our cases were represented by tumors with
spindle, giant cell, and/or squamoid patterns, alone or
in combination. Some authors regard squamous cell
carcinomas of the thyroid as separate from anaplastic
carcinoma.5 We agree with this concept when the entirety
of the tumor is of squamous cell type. In the cases here
included, however, the squamous component was only
focally present in tumors that were predominantly of
undifferentiated type, with frequent merging between
the two patterns. The distinction is largely academic in
any event, since the behavior of anaplastic and squamous
cell thyroid carcinomas is very similar.
The differential diagnosis of anaplastic carcinoma, in
addition to the above listed epithelial malignancies,
includes that of various soft tissue sarcomas. This is so
because the pattern of growth of anaplastic carcinoma
can simulate very closely those of fibrosarcoma, malig-
nant fibrous histiocytoma (including its inflammatory
and myxoid variants), malignant hemangiopericytoma,
and angiosarcoma. We take issue with the statement
made by the WHO Committee on Classification of
Thyroid Tumours 32 that the formation of intercellular
substance (such as collagen, reticulin, or osteoid) by
individual tumor cells is evidence that the tumor is a
sarcoma. We believe that it is only through the identi-
fication of obvious epithelial structures in other areas
that the carcinomatous nature of these tumors becomes
manifest. This raises the question as to whether it is
proper to designate as anaplastic carcinomas those thy-
roid tumors in which such epithelial areas are not found,
153
either because of incomplete sampling or simply because
they are not there. We favor this approach both on
morphologic and practical grounds. The sarcoma-like
areas look identical in all respects, whether a clear-cut
carcinomatous component is found elsewhere or not,
and the behavior of these tumors is also equivalent. A
possible morphologic clue as to the carcinomatous nature
of the tumor in the sarcoma-like spindle areas is the
presence of the peculiar pattern of invasion of the wall
of veins and arteries, a feature that we found prominently
displayed in many of our tumors. This "angiotropic"
quality, which we also have seen in sarcomatoid carci-
nomas of other organs, is seen less frequently in true
soft tissue sarcomas. Additional support may come from
examination of the tumor by special technics, such as
electron microscopy and immunohistochemistry. The
four major works on the ultrastructure of this
tumor 24,31,38,54 coincide in describing epithelial differen-
tiation in all of the cases, mainly manifested by frequent
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specialized cell junctions and arrays of microvilli pro-
jecting into intercellular spaces. We found similar features
in four of our cases, but not in the other three. We
interpreted the latter as due to total dedifferentiation of
the neoplasm, so that all epithelial markers were lost.
As a result, we could not have distinguished these three
neoplasms from soft tissue sarcomas on the basis of the
electron microscopy alone. A dramatic demonstration
of this phenomenon was provided by the case in which
we had the opportunity to compare the well-differentiated
carcinoma with the anaplastic tumor that followed it.
Thus, we agree with the above authors that electron
microscopy is very useful in the evaluation of these
neoplasms but also wish to point out its limitations.
Immunocytochemical stains for thyroglobulin, thy-
roxine, T 3 , and keratin also have been employed to
detect epithelial and, specifically, follicular differentiation
in these tumors. Positivity for thyroglobulin has been
reported in one out of 3 tumors, 46 one out of 11
tumors,10 four out of 10 tumors, 8 three out of 9 tumors,42
three out of 7 tumors, 44 and ten out of 14 tumors. 4
However, in most of the cases the reaction was described
as weak, focal, and restricted to only a few of the
neoplastic cells. In two series,8,44 it was seen only in the
follicles or papillae present within the tumor. Curiously
enough, the former authors observed staining for T 3 in
four of these cases, even in specimens with negativity
for thyroglobulin. Our results with thyroglobulin were
totally disappointing. We did not encounter convincing
positivity in tumor cells in any of the many tumors we
examined. Instead, we found that strongly staining,
entrapped nonneoplastic follicles and individual cells
constitute an important pitfall because they—especially
the latter—can be misinterpreted as neoplastic elements.
Another possible source of error is the diffusion of
154 CARCANGIU ET AL.
thyroglobulin that can occur from the entrapped follicles
and permeate the neighboring tumor cells, a feature
already pointed out by Kawaoi and associates,42 and
that has analogies to tumors in other sites.22 Whatever
the discrepancy between our results and those of previous
authors might be, we concluded that thyroglobulin
staining is of little use in the identification of anaplastic
thyroid carcinoma.
The positivity of some tumors with squamoid pattern
for CEA was surprising and unexplained. To the best of
our knowledge, this has not been recorded previously in
the literature, which lists the cells of medullary carcinoma
and related (follicular-parafollicular cell) tumors as the
only ones reacting to this antigen.45
Stains for epidermal-type keratin, with the use of a
polyclonal rabbit antibody, proved of only limited utility,
since they stained only a minority of the tumors and
usually only in the areas that appeared clearly epithelial
in the routinely stained preparations. Instead, staining
for cytokeratin, employing a monoclonal antibody,
showed a strong staining of anaplastic cells of spindle
and giant cell type in nearly half of our cases. Various
types of soft tissue sarcomas (malignant fibrous histio-
cytoma, liposarcoma, malignant schwannoma, angiosar-
coma) were negative for this antigen. Miettinen and
associates53 recorded even better results: all ten anaplastic
carcinomas they studied showed some tumor cells pos-
itive for cytokeratin (as well as vimentin), whereas only
two had scattered cells positive for antiepidermal-type
keratin. It would appear from our results and those of
Miettinen and associates53 that stain for cytokeratin,
using a monoclonal antibody, is the most effective way
to confirm the epithelial nature of an anaplastic thyroid
tumor.
It follows from the above considerations that the
diagnosis of sarcoma of any type should be made with
extreme caution when in the presence of a pleomorphic
malignant tumor located in the thyroid gland or in its
immediate surroundings. Actually, our attitude is to
regard any pleomorphic sarcoma-like tumor of the thy-
roid as anaplastic carcinoma, unless there is undeniable
proof to the contrary. A possible exception is angiosar-
coma or malignant hemangioendothelioma, a highly
controversial thyroid neoplasm reported almost exclu-
sively from Switzerland.19 Recent ultrastructural and
immunohistochemical evidence has been put forward
that suggests that a malignant thyroid tumor made up
of endothelial cells indeed exists.65 The fact still remains
that, outside this particular geographic location, the
overwhelming majority of thyroid malignancies having
a focal angiosarcoma-like appearance probably represent
anaplastic carcinomas.
The osteoclast-like giant cells that are seen in some
of the tumors, sometimes in abundance, are probably
AJ.C.P. • February 1985
not carcinomatous cells. Both their light and electron
microscopic appearance16 would seem to suggest that
they are instead nonneoplastic mesenchymal elements.
As such, they should be distinguished clearly from
multinucleated and otherwise bizarre tumor cells having
obvious nuclear atypicality. This osteoclast-like compo-
nent is analogous to that sometimes seen in sarcomatoid
carcinomas of other organs, such as breast,2 lung,58
pancreas,64 ovary,60 and salivary gland.23 Tumors with
this component often are accompanied by a myxochon-
droid stroma and, in some reported cases, even well-
developed cartilage and bone. 28 This capacity of the
tumor cells to differentiate toward skeletal-type tissues
might be responsible for the appearance of the multi-
nucleated cells, perhaps through a specific secretory
product of the tumor cell.47 We regard the thyroid
carcinomas containing osteoclast-like cells not as a
separate type of thyroid malignancy, as some authors
do, 16 but rather as a variant in the spectrum of anaplastic
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carcinoma. In support of this concept is the fact that
several of them are seen in association with a well-
differentiated thyroid malignancy.30 Furthermore, they
behave as a group just as aggressively as the anaplastic
thyroid carcinomas lacking this component. 68 Paren-
thetically, this contrasts with the behavior of osteoclast-
containing tumors in other epithelial organs, many of
which follow a rather indolent course.
The findings of this series support those from previous
studies by u s " and others29,37,67,79 to the effect that a
significant number of anaplastic carcinomas are asso-
ciated with a well-differentiated thyroid tumor. The two
patterns can be seen together in the initial pathologic
specimen, or the anaplastic carcinoma may develop
months or years following the removal of a well-differ-
entiated neoplasm. The incidence of well-differentiated
carcinoma (either coexistent with the anaplastic carci-
noma or preceding it) varies from 8.5%79 to 80%56 in
the literature. In our own series, it was 30%. Probably
some of the lower figures quoted represent underesti-
mates, either because the sampling was not thorough or
because the anaplastic component was so advanced that
it totally obscured the well-differentiated elements. These
factors also might explain the differences we encountered
among the Florence and Minnesota populations in this
regard. It may well be that all anaplastic carcinomas
arise from well-differentiated tumors, as some authors
have suggested.56 Aldinger and associates5 reported the
occasional coexistence of well-differentiated and ana-
plastic patterns in some metastatic foci and the fact
that, in some instances, the anaplastic transformation
supervened only in a distant metastatic focus. Nussbaum
and coworkers57 reported the unique case of an anaplastic
carcinoma arising from median ectopic thyroid (thyro-
glossal duct remnant).
Vol. 83 • No. 2 ANAPLASTIC THYROID CARCINOMA
All major types of thyroid carcinomas are susceptible
to this change: papillary, follicular, Hufthle's cell, poorly
differentiated (insular), and medullary. Papillary and
follicular carcinomas are by far the most common. In
some series the follicular tumors greatly predominate, 56
whereas in others the reverse is true.3,77 It is not clear
whether this represents a true difference, perhaps based
on geographic location, or simply the result of differences
in histopathologic diagnostic criteria.
There seems to be no relationship between the type
of well-differentiated carcinoma and the type of anaplastic
tumor that it may engender, except between papillary
carcinoma and the squamoid type of anaplastic carci-
noma. This should not be surprising, in view of the
tendency for the former tumor to undergo squamous
metaplasia12 and to be associated with the formation of
epidermal-type keratin.53 In this regard, it was of interest
to see that the typical ground glass appearance of the
nuclei of papillary carcinoma sometimes was maintained
in the squamoid foci, an observation already made by
Eisner and colleagues.20
The relationship between medullary carcinoma and
anaplastic carcinoma is somewhat complex and confus-
ing. We already have alluded to the variant of the
former composed of uniform small round cells, likely
to be confused with a malignant lymphoma or a small
cell undifferentiated carcinoma.48,52 There is also the
occasional medullary carcinoma in which areas with the
characteristic organoid pattern of this tumor type alter-
nate with others showing bizarre spindle and/or giant
cell formation. 4080 Finally, there is a recently published
remarkable observation55 concerning nine cases that
were, according to the authors, typical of spindle or
giant cell anaplastic thyroid carcinomas on clinical and
pathologic grounds. They found that as many as seven
(78%) of these tumors were argyrophilic with the Gri-
melius' technic and contained calcitonin with the im-
munoperoxidase technic. An additional case with similar
features subsequently was reported.49 If the results of
these studies are confirmed, this would mean that the
majority of anaplastic thyroid carcinomas are related to
medullary carcinoma and not, as widely believed, to
papillary and follicular tumors. Our results were quite
different. A few argyrophil cells were detected in several
tumors, but the coarse and focal nature of the granules,
the fact that these granules were particularly prominent
in the necrotic areas, and the occasional presence of
similar granules in the nonneoplastic follicular epithe-
lium, suggest to us that this finding had no specific
significance. More pertinently, the apparent positivity
for calcitonin seen in scattered cells of some cases could
not be abolished with preabsorption with purified antigen,
strongly suggesting that the reaction seen was of a
nonspecific nature and not indicative of the presence of
155
calcitonin in the tumor cells. Furthermore, dense-core
granules of calcitonin type were not seen in any of the
seven cases studied ultrastructurally. Thus, we have
strong reservations about the proposal that most ana-
plastic thyroid tumors are linked with medullary carci-
noma. From a practical standpoint, it also should be
noted that those tumors that have an anaplastic micro-
scopic appearance will behave in the fashion expected
for this group, whether signs of medullary differentiation
allegedly are detected in them or not. Thus, in the
above-quoted series,55 most of the patients with "ana-
plastic medullary carcinoma" died within six months
after the initial diagnosis was made.
Fortunately, the probability of an anaplastic transfor-
mation occurring in any of the well-differentiated thyroid
neoplasms is statistically so low as not to constitute a
serious consideration when deciding on the choice of
therapy. If the bulk of the tumor has an anaplastic
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appearance, we and most others37,79 have found that
there is no prognostic difference whether a residual well-
differentiated component is present or not. Eisner and
associates20 claimed to show a better prognosis for the
former, but the differences were not pronounced and
the number of cases relatively small. On the other hand,
if most of the tumor is well-differentiated and the
anaplastic elements are limited to a small microscopic
focus, the chances for cure are better, although far from
high.5 Only one of our cases belonged to the latter
category, and that patient died of tumor.
Some authors have suggested that anaplastic transfor-
mation of well-differentiated thyroid tumors may be
induced by the administration of radioactive iodine6,18
or external irradiation therapy.25 Kapp and associates41
were able to find 60 cases of this association. Whether
the radiation therapy is related causally to the anaplastic
transformation or not, the event is so rare that it should
not interfere with the administration of radiation therapy
(especially in the form of radioactive iodine) if this
appears indicated for control of unresectable, locally
recurrent, or metastatic well-differentiated thyroid car-
cinomas.41 On the other hand, we feel that this potential
danger should be kept in mind when considering pro-
phylactic administration of I|31 following surgical removal
of a papillary thyroid carcinoma, especially in view of
the fact that the benefit of this approach is far from
proven.12
Another antecedent mentioned in some series is a
history of long-standing goiter, the incidence given gen-
erally being in the neighborhood of 40%,5,39,75 but some-
times reaching much higher figures.56 Perhaps related to
this fact is the observation that anaplastic carcinoma
has a higher incidence in areas of endemic goiter34 and
that its frequency has decreased with the introduction
of iodine prophylaxis.36 In our series, there was a striking
 CARCANGIU ET AL.
156
difference in the incidence of preexisting diffuse or
nodular goiter depending on the geographic location:
30.8% for the Italian patients and only 3.2% for the 2.
individuals from Minnesota.
The therapy of anaplastic thyroid carcinoma generally
3.
yields dismal results, as this large group of cases clearly
shows. Surgical excision may be effective for the rare
tumors found as an incidental microscopic focus in an
4.
otherwise well-differentiated neoplasm, but it is almost
always unsuccessful (except for a temporary palliative
effect) in the clinically obvious tumors, most of which 5.
have spread beyond the thyroid at the time of initial
diagnosis. Suppression of thyroid function and admin-
istration of I13| are of no value. The former is to be 6.
expected, since the growth and metabolic activity of this
tumor—in contrast with the well-differentiated neo- 7.
plasms—have been shown to be independent of TSH,
8.
presumably through the loss of TSH receptors.1 Post-
operative external radiation therapy, although recom-
mended by most authors, generally has proved ineffective. 9.
One wonders whether the sporadic reports of cure with
this modality, especially in old series, are not the result 10.
of the mistaken inclusion of malignant lymphomas into
this category. This was clearly the case in our experience:
all the long-term survivors among our cases originally 11.
diagnosed as anaplastic carcinomas were found to rep-
resent malignant lymphomas on review.
12.
Many chemotherapeutic agents have been tried, singly
or in combination. This includes adriamycin, which
currently is regarded as the single most active agent
against thyroid carcinoma.59 Initial tumor regression 13.
can be obtained with some regularity, and this may
render a previously inoperable tumor amenable to sur- 14.
gical excision.71 However, in nearly all cases the tumor
quickly recurs and kills the patient in less than one year.
15.
An optimistic early report about the effects of the
combination of surgery, irradiation, and actinomycin 16.
D63 could not be duplicated in a subsequent study from
the same group.5 The best results in a nonrandomized 17.
series of 84 cases were reported by Aldinger and asso-
ciates5 seen in the group of 14 patients who had a 18.
combination of surgery, radiation therapy, and chemo-
therapy; there were four survivors, three of them older
than 50 years of age. However, most of these patients 19.
had only a focal anaplastic carcinoma in what was
otherwise a well-differentiated tumor. Several "new" or
"different" approaches have been offered in recent 20.
years,l4-43-69 but the results shown are far from satisfac-
tory. At present, it would seem that the best chances for 21.
cure, however slim, are obtained from the combination
of surgery, radiation therapy, and multidrug chemother- 22.
apy.575
23.
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